N-substituted sulfonamide derivatives

ABSTRACT

The present invention provides certain N-substituted sulfonamide derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.

This is a 371 of PCT/US99/17017 filed Jul. 28, 1999 which claimspriority to U.S. Provisional Application No. 60/094,921 filed Jul. 31,1998.

The present invention relates to the potentiation of glutamate receptorfunction using certain N-substituted sulfonamide derivatives. It alsorelates to novel N-substituted sulfonamide derivatives, to processes fortheir preparation and to pharmaceutical compositions containing them.

In the mammalian central nervous system (CNS), the transmission of nerveimpulses is controlled by the interaction between a neurotransmitter,that is released by a sending neuron, and a surface receptor on areceiving neuron, which causes excitation of this receiving neuron.L-Glutamate, which is the most abundant neurotransmitter in the CNS,mediates the major excitatory pathway in mammals, and is referred to asan excitatory amino acid (EAA). The receptors that respond to glutamateare called excitatory amino acid receptors (EAA receptors). See Watkins& Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). The excitatory amino acids are of great physiologicalimportance, playing a role in a variety of physiological processes, suchas long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiration, cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic”. This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), andkainic acid (KA). The second general type of receptor is the G-proteinor second messenger-linked “metabotropic” excitatory amino acidreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in c-AMP formation, and changesin ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci.,14, 13 (1993). Both types of receptors appear not only to mediate normalsynaptic transmission along excitatory pathways, but also participate inthe modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in PharmacolSci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

AMPA receptors are assembled from four protein sub-units known as GluR1to GluR4, while kainic acid receptors are assembled from the sub-unitsGluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, MolecularPharmacology 44: 505-510, 1993. It is not yet known how these sub-unitsare combined in the natural state. However, the structures of certainhuman variants of each sub-unit have been elucidated, and cell linesexpressing individual sub-unit variants have been cloned andincorporated into test systems designed to identify compounds which bindto or interact with them, and hence which may modulate their function.Thus, European patent application, publication number EP-A2-0574257discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B.European patent application, publication number EP-A1-0583917 disclosesthe human sub-unit variant GluR4B.

One distinctive property of AMPA and kainic acid receptors is theirrapid deactivation and desensitization to glutamate. Yamada and Tang,The Journal of Neuroscience, September 1993, 13(9): 3904-3915 andKathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647. Thephysiological implications of rapid desensitization, and deactivation ifany, are unknown.

It is known that the rapid desensitization and deactivation of AMPAand/or kainic acid receptors to glutamate may be inhibited using certaincompounds. This action of these compounds is often referred to in thealternative as “potentiation” of the receptors. One such compound, whichselectively potentiates AMPA receptor function, is cyclothiazide. Partinet al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiateAMPA receptors, like cyclothiazide, are often referred to as ampakines.

International Patent Application Publication Number WO 9625926 disclosesa group of phenylthioalkylsulfonamides, S-oxides and homologs which aresaid to potentiate membrane currents induced by kainic acid and AMPA.

U.S. Pat. No. 3,143,549 discloses certain phenylalkylsulfamides,including 1-methyl-2-phenylethyl dimethylsulfamide. The compounds aresaid to have central nervous system activity, in particular anti-anxietyand tranquilizing properties.

U.S. Pat. No. 3,267,139 discloses certainN′-trimethylacetyl-N-phenylalkylsulfamides and-phenylcyclopropylsulfamides having central nervous system activity andanticonvulsant activity. The compounds are also said to produceParkinson-like symptoms in experimental animals.

U.S. Pat. No. 3,860,723 discloses a method of increasing feed intake ofhealthy animals using certain phenylalkylsulfamides.

Foye et al., J. Pharm. Sci. (1971), 60(7), 1095-6 discloses certainphenylalkyl methylsulfonamides including N-1-methyl-2-phenylethylmethanesulfonamide, having hypotensive activity.

British Patent Specification Number 1,059,360 discloses certainphenylalkylsulfamides having activity as sedatives, narcotics andanti-convulsants, including1-(1-methyl-2-phenylethylaminosulphonyl)piperidine.

U.S. Pat. No. 4,210,749 discloses N-1-methyl-2-phenyl-3-methoxy ethylbutane-sulfonamide.

Gualtieri et al., J. Pharm. Sci., (1973), 62(5), 849-851 disclosesN-1-methyl-2-phenylethyl butanesulfonamide and its evaluation as amosquito repellent.

Foye et al., J. Pharm. Sci. (1979), 68(5), 591-5 disclosesN-1-methyl-2-(4-chlorophenyl)ethyl methane-sulfonamide.

Foye and Sane, J. Pharm. Sci. (1977), 66(7), 923-6 disclosesN-methanesulfonyl and N-trifluoromethanesulfonyl derivatives ofamphetamines and certain 4-substituted analogs thereof, and theirevaluation for central nervous system and anorexic effects.

European patent application publication no. EP-A1-0657442 disclosescertain naphthyloxyacetic acid derivatives as PEG2 agonists andantagonists. N-(2,2-diphenylethyl)-methanesulfonamide is disclosed as anintermediate at page 53, line 38.

U.S. Pat. No. 3,629,332 discloses certain N-aryl- and N-heteroarylalkylfluoroalkane sulfonamides as plant growth modifiers, includingN-(alpha-methylphenylethyl) trifluoromethanesulfonamide,difluoromethanesulfonamide and fluoromethanesulfonamide. Some of thecompounds are also said to have other biological activity, includinginsecticidal, acaricidal, nematicidal, analgesic and anti-inflammatoryactivity.

Ampakines have been shown to improve memory in a variety of animaltests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777-781,1994, Neurobiology, and Arai et al., The Journal of Pharmacology andExperimental Therapeutics, 278: 627-638,1996.

It has now been found that cyclothiazide and certain N-substitutedsulfonamide derivatives potentiate agonist-induced excitability of humanGluR4B receptor expressed in HEK 293 cells. Since cyclothiazide is knownto potentiate glutamate receptor function in vivo, it is believed thatthis finding portends that the N-substituted sulfonamide derivativeswill also potentiate glutamate receptor function in vivo, and hence thatthe compounds will exhibit ampakine-like behavior.

The present invention provides compounds of formula I:

wherein

R^(a) represents (1-6C)alkyl, CO(1-6C)alkyl, CO(aryl), CO₂(1-6C)alkyl,CO₂(1-6C)alkylaryl, CO₂(aryl), COCH₂OH, CH(1-6C)O₂C(1-6C)alkyl,CO(1-6C)alkylNH(1-6C)alkyl, CO(1-6C)alkylN(1-6C)alkyl₂, andCO(1-6C)alkylNR^(e)R^(f) wherein R^(e) and R^(f) together with thenitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl oroctahydroazocinyl group;

R¹ represents a naphthyl group or a phenyl, furyl, thienyl or pyridylgroup which is unsubstituted or substituted by one or two substituentsselected independently from halogen; nitro; cyano; hydroxyimino;(1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO orOCONR¹³, R⁹ represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl,(3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl;(1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group;

R² represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoro-alkyl,(1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl,(1-4C)alkylCO₂(1-4C)alkyl, heteroaromatic, phenyl which is unsubstitutedor substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group offormula R³R⁴N in which R³ and R⁴ each independently represents(1-4C)alkyl or, together with the nitrogen atom to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino,piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and

R⁵, R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl;aryl(2-6C)alkenyl and aryl; or

two of R⁵, R⁶, R⁷ and R⁸ together with the carbon atom or carbon atomsto which they are attached form a (3-8C) carbocyclic ring; and theremainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or a pharmaceuticallyacceptable salt thereof.

The present invention provides a method of potentiating glutamatereceptor function in a mammal requiring such treatment, which comprisesadministering an effective amount of a compound of formula I.

According to another aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof asdefined hereinabove for the manufacture of a medicament for potentiatingglutamate receptor function.

According to yet another aspect, the present invention provides the useof a compound of formula I or a pharmaceutically acceptable salt thereofas defined hereinabove for potentiating glutamate receptor function.

The present invention further provides a method of potentiatingglutamate receptor function in a mammal requiring such treatment, whichcomprises administering an effective amount of a compound of formula:

wherein

R^(a) represents (1-6C)alkyl, CO(1-6C)alkyl, CO(aryl), CO₂(1-6C)alkyl,CO₂(1-6C)alkylaryl, CO₂(aryl), COCH₂OH, CH(1-6C)O₂C(1-6C)alkyl,CO(1-6C)alkylNH(1-6C)alkyl, CO(1-6C)alkylN(1-6C)alkyl₂, andCO(1-6C)alkylNR^(e)R^(f) wherein R^(e) and R^(f) together with thenitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl oroctahydroazocinyl group;

R¹ represents an unsubstituted or substituted aromatic or heteroaromaticgroup; R² represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoro-alkyl,(1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl,(1-4C)alkylCO₂(1-4C)alkyl, heteroaromatic, phenyl which is unsubstitutedor substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group offormula R³R⁴N in which R³ and R⁴ each independently represents(1-4C)alkyl or, together with the nitrogen atom to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino,piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and R⁵, R⁶,R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyland aryl; or

two of R⁵, R⁶, R⁷ and R⁸ together with the carbon atom or carbon atomsto which they are attached form a (3-8C) carbocyclic ring; and theremainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen; or a pharmaceuticallyacceptable salt thereof.

In this specification, the term “potentiating glutamate receptorfunction” refers to any increased responsiveness of glutamate receptors,for example AMPA receptors, to glutamate or an agonist, and includes butis not limited to inhibition of rapid desensitisation or deactivation ofAMPA receptors to glutamate.

A wide variety of conditions may be treated or prevented by thecompounds of formula I and their pharmaceutically acceptable saltsthrough their action as potentiators of glutamate receptor function.Such conditions include those associated with glutamate hypofunction,such as psychiatric and neurological disorders, for example cognitivedisorders; neuro-degenerative disorders such as Alzheimer's disease;age-related dementias; age-induced memory impairment; movement disorderssuch as tardive dyskinesia, Hungtington's chorea, myoclonus andParkinson's disease; reversal of drug-induced states (such as cocaine,amphetamines, alcohol-induced states); depression; attention deficitdisorder; attention deficit hyperactivity disorder; psychosis; cognitivedeficits associated with psychosis; and drug-induced psychosis. Thecompounds of formula I may also be useful for improving memory (bothshort term and long term) and learning ability. The present inventionprovides the use of compounds of formula I for the treatment of each ofthese conditions.

The term “treating” (or “treat”) as used herein includes its generallyaccepted meaning which encompasses prohibiting, preventing, restraining,and slowing, stopping, or reversing progression, severity, or aresultant symptom.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined by formula I. A compound of this invention canpossess a sufficiently acidic, a sufficiently basic, or both functionalgroups, and accordingly react with any of a number of organic andinorganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds of the above formula which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid oran organic or inorganic base. Such salts are known as acid addition andbase addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, g-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that the above salts may form hydratesor exist in a substantially anhydrous form.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formula I can be resolved by one of ordinary skill in the art usingstandard techniques well known in the art, such as those described by J.Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wileyand Sons, Inc., 1981. Examples of resolutions include recrystallizationtechniques or chiral chromatography.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

As used herein, the term “aromatic group” means the same as aryl, andincludes phenyl and a polycyclic aromatic carbocyclic ring such asnaphthyl.

The term “heteroaromatic group” includes an aromatic 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen, and a bicyclic group consisting of a 5-6 membered ringcontaining from one to four heteroatoms selected from oxygen, sulfur andnitrogen fused with a benzene ring or another 5-6 membered ringcontaining one to four atoms selected from oxygen, sulfur and nitrogen.Examples of heteroaromatic groups are thienyl, furyl, oxazolyl,isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, indolyl and quinolyl.

The term “substituted” as used in the term “substituted aromatic orheteroaromatic group” herein signifies that one or more (for example oneor two) substituents may be present, said substituents being selectedfrom atoms and groups which, when present in the compound of formula I,do not prevent the compound of formula I from functioning as apotentiator of glutamate receptor function.

Examples of substituents which may be present in a substituted aromaticor heteroaromatic group include halogen; nitro; cyano; hydroxyimino;(1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R¹¹, R¹² and R¹³ each independently represents hydrogen or (1-10C)alkyl,or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogen atom to whichthey are attached form an azetidinyl, pyrrolidinyl, piperidinyl ormorpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyl dihydrothiazolyl;(1-4C)alkoxycarbonyl dimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH, orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen;nitro; cyano; (1-10C) alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; and (CH₂)_(z)X³R¹⁵ inwhich z is 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO,CH(OH), COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, OCONR¹⁹ or NR¹⁹COO,R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl, or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.

The term (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl.Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

The term (2-10C)alkenyl includes (3-10C)alkenyl, (1-8C)alkenyl,(1-6C)alkenyl and (1-4C)alkenyl. Particular values are vinyl andprop-2-enyl.

The term (2-10C)alkynyl includes (3-10C)alkynyl, (1 8C)alkynyl,(1-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.

The term (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy,includes monocyclic and polycyclic groups. Particular values arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andbicyclo[2.2.2]octane. The term includes (3-6C)cycloalkyl: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term hydroxy(3-8C)cycloalkyl includes hydroxy-cyclopentyl, such as3-hydroxycyclopentyl.

The term oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as3-oxocyclopentyl.

The term halogen includes fluorine, chlorine, bromine and iodine.

The term halo(1-10C)alkyl includes fluoro(1-10C)alkyl, such astrifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-10C)alkyl such aschloromethyl.

The term cyano(2-10C)alkenyl includes 2-cyanoethenyl.

The term (2-4C)alkylene includes ethylene, propylene and butylene. Apreferred value is ethylene.

The term thienyl includes thien-2-yl and thien-3-yl.

The term furyl includes fur-2-yl and fur-3-yl.

The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.

The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl andisoxazol-5-yl.

The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and[1,2,4]oxadiazol-5-yl.

The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.

The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.

The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and[1,2,4]thiadiazol-5-yl.

The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl andisothiazol-5-yl.

The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl andimidazolyl-5-yl.

The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.

The term tetrazolyl includes tetrazol-5-yl.

The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl,pyridazin-5-yl and pyridazin-6-yl.

The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl and pyrimidin-6-yl.

The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.

The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.

The term benzimidazolyl includes benzimidazol-2-yl.

The term benzoxazolyl includes benzoxazol-2-yl.

The term benzothiazolyl includes benzothiazol-2-yl.

The term indolyl includes indol-2-yl and indol-3-yl.

The term quinolyl includes quinol-2-yl.

The term dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl, and the term(1-4C)alkoxycarbonyldihydrothiazolyl includes4-methoxycarbonyl4,5-dihydrothiazol-2-yl.

Preferably R^(a) represents methyl, ethyl, propyl, n-butyl, sec-butyl,methoxycarbonyl, t-butyoxycarbonyl, pivaloyloxymethyl, pivaloyloxyethyl,(((N,N-dimethylamino)ethyl)oxy)carbonyl, or(((morpholino)ethyl)oxy)carbonyl.

More preferably R^(a) represents methyl, t-butyoxycarbonyl,pivaloyloxymethyl, (((N,N-dimethylamino)ethyl)oxy)carbonyl or(((morpholino)ethyl)oxy)carbonyl.

Preferably either one or two of R⁵, R⁶, R⁷ and R⁸ represents(1-6C)alkyl, aryl(1-6C)alkyl, (2-6C)alkenyl, aryl(2-6C)alkenyl or aryl,or two of R⁵, R⁶, R⁷ and R⁸ together with the carbon atom or carbonatoms to which they are attached form a (3-8C)carbocyclic ring; and theremainder of R⁵, R⁶, R⁷ and R⁸ represent hydrogen.

Examples of a (1-6C)alkyl group represented by R⁵, R⁶, R⁷ and R⁸ aremethyl, ethyl and propyl. An example of an aryl(1-C)alkyl group isbenzyl. An example of a (2-6C)alkenyl group is prop-2-enyl. An exampleof a (3-8C)carbocyclic ring is a cyclopropyl ring.

More preferably R⁶ and R⁷ represent hydrogen.

Preferably R⁵ and R⁸ each independently represents hydrogen or(1-4C)alkyl, or together with the carbon atom to which they are attachedform a (3-8C) carbocyclic ring.

More preferably R⁸ represents methyl or ethyl, or R⁵ and R⁸ togetherwith the carbon atom to which they are attached form a cyclopropyl ring.When R⁸ represents methyl or ethyl, R⁵ preferably represents hydrogen ormethyl.

Especially preferred are compounds in which R⁸ represents methyl and R⁵,R⁶ and R⁷ represent hydrogen.

Preferably R³ and R⁴ each represent methyl.

Examples of values for R² are methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl,chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl,4-fluorophenyl, or dimethylamino. Preferably R² is ethyl, 2-propyl ordimethylamino.

Examples of values for R⁹ are hydrogen, methyl, ethyl, propyl,isopropyl, t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2-pyrrolidinyl, morpholino or 2-tetrahydrofuryl.

Examples of values for R¹⁵ are hydrogen, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, benzyl, 2,2,2-trifluoroethyl,2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl, phenyl,2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 1-(5-dimethylamino)naphthyl, and 2-thienyl.

X¹ preferably represents O, CO, CONH or NHCO.

z is preferably 0.

R⁹ is preferably (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl,pyrrolidinyl, morpholino or tetrahydrofuryl.

Particular values for the groups (CH₂)_(y)X¹R⁹ and (CH₂)_(z)X³R¹⁵include (1-10C)alkoxy, including (1-6C)alkoxy and (1-4C)alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy and isobutoxy; (3-10C)alkenyloxy,including (3-6C)alkenyloxy, such as prop-2-enyloxy; (3-10C)alkynyloxy,including (3-6C)alkynyloxy, such as prop-2-ynyloxy; and (1-6C)alkanoyl,such as formyl and ethanoyl.

Examples of particular values for y are 0 and 1.

Examples of particular values for z are 0 1, 2 and 3.

L^(a) and L^(b) preferably each independently represents CH₂.

X² preferably represents a bond, O, NH, CO, CH(OH), CONH, NHCONH orOCH₂CONH.

Preferably the group (CH₂)_(y)X¹R⁹ represents CHO; COCH₃, OCH₃;OCH(CH₃)₂; NHCOR⁹ in which R⁹ represents methyl, ethyl, isopropyl,t-butyl, ethenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyrolidinyl or morpholino; CONHR⁹ in which R⁹ represents cyclopropylor cyclopentyl; NHCOCOOCH3; or 2-tetrahydrofurylmethoxy.

Preferably the group (CH₂)_(z)X³R¹⁵ represents NH₂; CH₂NH₂; (CH₂)₂NH₂;(CH₂)₃NH₂; CONH₂; CONHCH₃; CON(CH₃)₂; N(C₂H₅)₂; CH₂OH; CH(OH)CH₃;CH(OH)CH₂CH₂; CHO; COCH₃; COOH; COOCH₃; CH₂NHCOOC(CH₃)₃;(CH₂)₂NHCOOC(CH₃)₃; NHSO₂CH(CH₃)₂; a group of formula (CH₂)₂NHSO₂R¹⁵ inwhich R¹⁵ represents CH₃, CH₂CH₃, CH(CH₃)₂, (CH₂)₂CH₃, (CH₃)₃CH₃,benzyl, CH₂CF₃, 2-methoxycarbonylethyl, cyclohexyl, 10-camphoryl,phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-methoxyphenyl, 1-(2-dimethylamino)naphthyl or2-thienyl; CH(OH)CH₂NHSO₂CH₃; (CH₂)₃NHSO₂CH(CH₃)₂;COCH₂N(OCOC(CH₃)₂SO₂CH₃; COCH₂NHSO₂CH₃; (CH₂)₂NHCOR¹⁵ in which R¹⁵represents CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, phenyl, 3-fluorophenyl,4-fluorophenyl, benzyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-thienyl,CH═CH, CH═CHCN, OCH₃ or O(CH₂)₃CH₃.

Examples of particular values for (L^(a))_(n)—X²—(L^(b))_(m) are a bond,O, NH, S, SO, SO₂, CO, CH₂, COCH₂, COCONH, CH(OH)CH₂, CONH, NHCO,NHCONH, CH₂O, OCH₂, OCH₂CONH, CH₂NH, NHCH₂ and CH₂CH₂.

R¹⁴ is preferably an unsubstituted or substituted phenyl, naphthyl,furyl, thienyl, isoxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrimidylbenzothienyl or benzothiazolyl group.

Examples of particular values for R¹⁴ are phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-difluoro-phenyl, 2,4-difluorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-cyanophenyl, 3-nitrophenyl,4-hydroxyiminophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl,3-propylphenyl, 4-t-butylphenyl, 2-prop-2-enylphenyl,4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-bromomethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-(2-cyanoethenyl)phenyl, 4-phenyl,2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 2-acetylphenyl,3-acetylphenyl, 4-acetylphenyl, 2-propanoylphenyl,2-(2-methyl-propanoyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-butoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-(1-hydroxyethyl)phenyl,3-(1-hydroxyethyl)phenyl, 4-(1- hydroxyethyl)phenyl,2-(1-hydroxypropyl)phenyl, 4-(1-hydroxypropyl)phenyl,2-(1-hydroxy-2,2-dimethyl-propyl)phenyl, 4-trifluoromethoxyphenyl,2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl,4-aminomethylphenyl, 4-(2-aminoethyl)phenyl, 4-(3-aminopropyl)phenyl,4-carboxyphenyl, 4-carbamoylphenyl, 4-N-methylcarbamoylphenyl,4-N,N-dimethylcarbamoylphenyl, 2-isopropylaminomethylphenyl,4-t-butoxycarbonylaminomethylphenyl,4-(2-isopropoxy-carboxamido)ethylphenyl,4-(2-t-butoxycarboxamido)ethyl-phenyl, 4-isopropylsulfonylaminophenyl,4-(2-methane-sulfonylamino)ethylphenyl,4-(2-ethylsulfonylamino)ethyl-phenyl,4-(3-isopropylsulfonylamino)propylphenyl,4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl,4-(2-propylsulfonyl-amino)ethylphenyl,4-(2-isopropylsulfonylamino)ethylphenyl,4-(2-butylsulfonylamino)ethylphenyl,4-(1-isopropyl-sulfonylaminomethyl)ethylphenyl,4-(1-hydroxy-2-methane-sulfonylamino)ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonylamino)-ethylphenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylamino)-ethylphenyl,4-(2-N,N-dimethylaminosulfonylamino)-ethylphenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonyl-amino)ethyl)phenyl,4-(2-phenylacetamido)ethyl)phenyl, 4-methanesulfonylaminoethanoylphenyl,4-(N-(t-butoxy-carbonyl)methanesulfonylaminoethanoyl)phenyl,4-(2-(2-thienylcarboxamido)ethyl)phenyl, thien-2-yl,5-hydroxy-methylthien-2-yl, 5-formylthien-2-yl, thien-3-yl,5-hydroxymethylthien-3-yl, 5-formylthien-3-yl, 2-bromothien-3-yl,fur-2-yl, 5-nitrofur-2-yl, fur-3-yl, isoxazol-5-yl,3-bromoisoxazol-5-yl, isoxazol-3-yl, 5-trimethylsilylisoxazol-3-yl,5-methylisoxazol-3-yl, 5-hydroxymethylisoxazol-3-yl,5-methyl-3-phenylisoxazol4-yl, 5-(2-hydroxyethyl)isoxazol-3-yl,5-acetylisoxazol-3-yl, 5-carboxyisoxazol-3-yl,5-N-methylcarbamoylisoxazol-3-yl, 5-methoxycarbonylisoxazol-3-yl,3-bromo[1,2,4]oxadiazol-5-yl, pyrazol-1-yl, thiazol-2-yl,4-hydroxymethylthiazol-2-yl, 4-methoxycarbonylthiazol-2-yl,4-carboxythiazol-2-yl, imidazol-1-yl, 2-sulfhydryl-imidazol-1-yl,[1,2,4]triazol-1-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,2-ethyltetrazol-5-yl, 2-isopropyl-tetrazol-5-yl,2-(2-propenyl)tetrazol-5-yl, 2-benzyl-tetrazol-5-yl, pyrid-2-yl,5-ethoxycarbonylpyrid-2-yl, pyrid-3-yl, 6-chloropyrid-3-yl, pyrid-4-yl,5-trifluoro-methylpyrid-2-yl, 6-chloropyridazin-3-yl,6-methylpyridazin-3-yl, 6-methoxypyrazin-3-yl, pyrimidin-5-yl,benzothien-2-yl, benzothiazol-2-yl, and quinol-2-yl.

Examples of an unsubstituted or substituted aromatic or heteroaromaticgroup represented by R¹ are unsubstituted or substituted phenyl, furyl,thienyl (such as 3-thienyl) and pyridyl (such as 3-pyridyl).

More preferably, R¹ represents 2-naphthyl or a group of formula

in which

R²⁰ represents halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl;(2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cyclo-alkyl;hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl;(CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1 to 4, X¹represents O, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOO, OCONR¹³,R⁹ represents hydrogen, (1-10C) alkyl, (3-10C)alkenyl, (3-10C)alkynyl,pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R¹⁰,R¹¹, R¹² and R¹³ each independently represents hydrogen or (1-10C)alkyl,or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together with the nitrogen atom to whichthey are attached form an azetidinyl, pyrrolidinyl, piperidinyl ormorpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; tetrazolyl; pyridyl; pyridazinyl;pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl;dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyl-dihydrothiazolyl;(1-4C)alkoxycarbonyldimethyl-dihydrothiazolyl; tetrahydrothienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; benzothiazolyl; and a group offormula R¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O,NH, S, SO, SO₂, CO, CH(OH), CONH, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, NHCO, L^(a) and L^(b) each represent (1-4C)alkylene, one of n andm is 0 or 1 and the other is 0, and R¹⁴ represents a phenyl orhetero-aromatic group which is unsubstituted or substituted by one ortwo of halogen; nitro; cyano; (1-10C)alkyl; (2-10C)alkenyl;(2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl);halo(1-10C)alkyl; cyano(2-10C)alkenyl; phenyl; (CH₂)_(z)X³R¹⁵ in which zis 0 or an integer of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH),COO, OCO, CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO,R¹⁵ represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl,halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy, and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and

R²¹ represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group or a(1-4C)alkoxy group.

Examples of particular values for R²⁰ are fluorine, chlorine, bromine,cyano, hydroxyimino, methyl, ethyl, propyl, 2-propyl, butyl,2-methylpropyl, 1,1-dimethylethyl, cyclopentyl, cyclohexyl,3-hydroxycyclopentyl, 3-oxocyclopentyl, methoxy, ethoxy, propoxy,2-propoxy, acetyl, acetylamino, ethylcarboxamido, propylcarboxamido,1-butanoylamido, t-butylcarboxamido, acryloylamido,2-pyrrolidinylcarboxamido, 2-tetrahydrofurylmethoxy,morpholinocarboxamido, methyloxalylamido, cyclo-propylcarboxamido,cyclobutylcarboxamido, cyclopentyl-carboxamido, cyclohexylcarboxamido,cyclopropylcarbamoyl, cyclopentylcarbamoyl, pyrrolidin-1-yl, morpholino,piperidin-1-yl, N-methylpiperazinyl, N-benzylpiperazinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, isoxazol-3-yl, thiazol-2-yl, tetrazol-5-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydro-4-methoxycarbonylthiazol-2-yl,4,5-dihydro4-methoxy-carbonyl-5,5-dimethylthiazol-2-yl, benzothien-2-yl,benzothiazol-2-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl,2,3-difluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 2-methylphenyl,4-methylphenyl, 4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl,3-trifluoromethylphenyl, 4-trifluoro-methylphenyl,4-(2-cyanoethenyl)phenyl, 2-formylphenyl, 3-formylphenyl,4-formylphenyl, 3-acetylphenyl, 4-acetylphenyl, 4-carboxyphenyl,2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxymethylphenyl,4-hydroxymethylphenyl, 3-(1-hydroxyethyl)phenyl,4-(1-hydroxyethyl)phenyl, 4-(1-hydroxypropyl)phenyl, 2-aminophenyl,4-aminophenyl, 4-N,N-diethylaminophenyl, 4-aminomethylphenyl,4-(2-aminoethyl)-phenyl, 4-(3-aminopropyl)phenyl,4-(2-acetylaminoethyl)-phenyl, 4-t-butoxycarboxylaminoethyl)phenyl,4-(2-t-butoxycarboxylaminoethyl)phenyl, benzylsulfonylamino,4-isopropylsulfonylaminophenyl, 4-(2-methanesulfonylaminoethyl)phenyl,4-(2-ethylsulfonylaminoethyl)phenyl,4-(2-propylsulfonylaminoethyl)phenyl,4-(2-butylsulfonyl-aminoethyl)phenyl,4-(2-isopropylsulfonylaminoethyl)phenyl,4-(1-hydroxy-2-methanesulfonylaminoethyl)phenyl,4-(2-dimethylaminosulfonylaminoethyl)phenyl,4-(1-(2-(2-propyl)sulfonylaminopropyl)phenyl,4-(2-(2,2,2-trifluoroethyl)sulfonylaminoethyl)phenyl,4-(2-cyclohexylsulfonyl-aminoethyl)phenyl,4-(2-phenylsulfonylaminoethyl)phenyl,4-(2-(2-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(4-fluorophenyl)sulfonylaminoethyl)phenyl,4-(2-(2-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-trifluoromethylphenyl)sulfonylaminoethyl)phenyl,4-(2-(4-methoxyphenyl)sulfonylaminoethyl)phenyl,4-(2-(1-(5-dimethylamino)napthalenesulfonylamino)ethyl)phenyl,4-(2-(2-thienyl)sulfonylamino)ethyl)phenyl, 4-(2-benzamidoethyl)-phenyl,4-(2-(4-fluorobenzamido)ethyl)phenyl,4-(2-(3-methoxybenzamido)ethyl)phenyl,4-(2-(3-fluorobenzamido)-ethyl)phenyl,4-(2-(4-methoxybenzamido)ethyl)phenyl,4-(2-(2-methoxybenzamido)ethyl)phenyl,4-(2-(2-thienyl-carboxamido)ethyl)phenyl, 4-carbamoylphenyl,4-methyl-carbamoylphenyl, 4-dimethylcarbamoylphenyl,4-(2-(2-methylpropaneamido)ethyl)phenyl,4-(2-(3-methyl-butaneamido)ethyl)phenyl, benzoylmethyl, benzamido,2-fluorobenzamido, 3-flurobenzamido, 4-fluorobenzamido,2,4-difluorobenzamido, 3-chlorobenzamido, 4-chlorobenzamido,4-bromobenzamido, 4-iodobenzamido, 4-cyanobenzamido, 3-methylbenzamido,4-methylbenzamido, 4-ethylbenzamido, 4-propylbenzamido,4-t-butylbenzamido, 4-vinylbenzamido, 2-trifluoromethylbenzamido,3-trifluoromethylbenzamido, 4-trifluoromethylbenzamido,2-fluoro-4-trifluoromethylbenzamido, 2-methoxybenzamido,3-methoxybenzamido, 4-methoxybenzamido, 4-butoxybenzamido,4-phenylphenyl-carboxamido, 4-benzylcarboxamido,4-phenoxymethyl-carboxamido, 2-fluorobenzylamino, benzyloxy,2-fluorobenzyloxy, 2-hydroxy-2-phenylethyl, 2-fluorophenylcarbamoyl,4-(1-(2-(2-methoxycarbonylethanesulfonylamino)ethyl)phenyl,4-(1-(2-(10-camphorsulfonylamino)ethyl)phenyl,4-(1-(2-(benzylsulfonylamino)ethyl)phenyl,4-(2-phenylacetamido)-ethyl)phenyl,4-(methanesulfonylaminoethanoyl)phenyl,4-(N-t-butoxycarbonyl)methanesulfonylaminoethanoyl)phenyl,2-thienylcarboxamido, 2-furylcarboxamido,3-(5-methyl-isoxazolyl)carboxamido, 5-isoxazolylcarboxamido,2-benzothienylcarboxamido, 4-(5-methyl-3-phenylisoxazolyl)-carboxamido,4-pyridylcarboxamido, 2-(5-nitrofuryl)-carboxamido,2-pyridylcarboxamido, 6-chloro-2-pyridyl-carboxamido,2-thienylsulfonamido, 2-thienylmethylamino, 3-thienylmethylamino,2-furylmethylamino, 3-furylmethylamino, 3-acetylureido and2-(2-thienyl)ethylureido.

Examples of particular values for R²¹ are hydrogen and chlorine. R²¹ ispreferably ortho to R²⁰.

Examples of particular values for R¹ are 2-naphthyl, 4-bromophenyl,4-cyanophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropyl-phenyl,4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl,4-cyclopentylphenyl, 4-cyclohexylphenyl,4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)-phenyl,4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)-phenyl,4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl,4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl,4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluoro-phenyl)phenyl,4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)-phenyl,4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl and4-(2-methoxyphenyl)phenyl.

The compounds of formula I can be prepared from compounds of formula II.Compounds of formula II can be prepared, for example, as described inScheme I below. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. All the substituents,unless otherwise specified are previously defined.

In Scheme I, the compound of formula III is reacted with the compound offormula IV under standard conditions well known in the art to providethe compound of formula II. The leaving atom or group represented by Lgmay be, for example, a halogen atom such as a chlorine or bromine atom.The reaction is conveniently performed in the presence of a base, forexample an alkali metal hydroxide, such as sodium hydroxide, an alkalimetal carbonate such as potassium carbonate, or a tertiary amine such astriethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. Suitable solventsinclude halogenated hydrocarbons such as dichloromethane. The reactionis conveniently performed at a temperature in the range of from −20 to100° C., preferably from −5 to 50° C.

In addition, the compounds of formula II in which R¹ represents a4-bromophenyl group may conveniently be converted into other compoundsof formula II in which R represents another 4-substituted phenyl groupby reaction with an appropriate boronic acid derivative, for example, abenzeneboronic acid derivative. The reaction is conveniently performedin the presence of a tetrakis (triarylphosphine)palladium(0) catalyst,such as tetrakis (triphenylphosphine)palladium(0) and a base such aspotassium carbonate. Convenient solvents for the reaction includearomatic hydrocarbons, such as toluene. The temperature at which thereaction is conducted is conveniently in the range of from 0 to 150° C.,preferably 75 to 120° C. Bis aromatic intermediates useful in thepreparation of compounds of formula II may be prepared by reacting abromoaromatic or bromoheteroaromatic compound with an aromatic orheteroaromatic boronic acid in an analogous manner.

The boronic acid derivative used as a starting material may be preparedby reacting a trialkyl borate, such as triisopropyl borate with anappropriate organolithium compound at reduced temperature. For example,2-fluorobenzeneboronic acid may be prepared by reacting2-fluorobromobenzene with butyllithium in tetrahydrofuran at about −78°C. to afford 2-fluorophenyl lithium, and then reacting thisorganolithium compound with triisopropyl borate.

Alternatively, the compounds of formula II in which R¹ represents a4-bromophenyl group may be converted to a 4-(trimethylstannyl)phenyl or4-(tri-n-butylstannyl)phenyl group by treatment of the correspondingbromide with a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and hexaalkyldistannane, wherethe alkyl group is methyl or n-butyl, in an aprotic solvent such astoluene in the presence of a tertiary amine base such as triethylamine,at temperatures ranging from 80 to 140° C., preferably from 90 to 110°C.

The compounds of formula II in which R¹ represents a4-(tri-n-butylstannyl)phenyl group may then be reacted with an aryl- orheteroarylbromide, such as 2-bromothiophene-5-carboxaldehyde, in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), or a palladium(II) catalyst,such as bis(triphenylphosphine)-palladium(II) dichloride, in an aproticsolvent, such as dioxane, at temperatures ranging from 80 to 140° C.,preferably from 90 to 110° C., to afford the corresponding4-(aryl)phenyl or 4-(heteroaryl)phenyl substituted compound.

The compounds of formula II in which R¹ represents a 4-bromophenyl groupmay be converted into other compounds of formula II in which R¹represents a 4-substituted alkyl- or cycloalkylphenyl group, such as4-cyclopentylphenyl by treatment of the corresponding bromide with anappropriate alkyl- or cycloalkyl Grignard reagent, such ascyclopentyl-magnesium bromide, in the presence of a palladium(II)catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(PdCl₂(dppf)),in an aprotic solvent, such as diethyl ether at temperatures rangingfrom −78° C. to 25° C.

The compounds of formula II in which R¹ represents a 4-bromophenyl groupmay be converted into a 4-substitutedcarboxyaldehydephenyl(formylphenyl) group by reaction of thecorresponding bromide with the carbon monoxide gas which is bubbled intothe reaction under atmospheric pressure in the presence of apalladium(II) catalyst, such as bis(triphenylphosphine)palladium(II)dichloride and sodium formate in an aprotic solvent, such asdimethylformamide at temperatures ranging from 70 to 110° C., preferablyat 90° C.

The compounds of formula II in which R¹ represents a 4-hydroxyphenylgroup may be converted into other compounds of formula I in which R¹represents an alkoxy group by treatment of the correspondinghydroxyphenyl group with an appropriate alkylhalide such asbenzylbromide in the presence of sodium hydride in an aprotic solventsuch as dimethylformamide at temperatures ranging from 25 to 100° C.,preferably from 50 to 90° C.

The compounds of formula III are known or may be prepared byconventional methods, for example by reducing a corresponding amide ornitrile using borane.

Some of the nitriles or amides used as starting materials mayconveniently be prepared by treatment of an acetonitrile of formulaR¹CH₂CN, for example a substituted phenylacetonitrile such as4-methoxyphenylacetonitrile or an acetate of formula R¹CH₂COOR (where Ris, for example alkyl), for example a phenylacetate such as methyl4-tert-butylphenylacetate, with a strong lithium amide base, such assodium or lithium bis(trimethylsilyl)amide, and an alkylhalide, such asmethyl iodide, in an aprotic solvent, such as tetrahydrofuran, at atemperature ranging from −78 to 25° C. The esters are converted toamides by hydrolysis (water, alcohol and sodium or potassium hydroxide)to the acid, conversion of the acid to the acid chloride (SOCl₂ or(COCl)₂ plus DMF (1 drop)) then conversion to the amide with aqueousammonia and a co-solvent such as tetrahydrofuran or dioxane.

Certain nitrites used to prepare compounds of formula III may alsoconveniently be prepared by reacting a corresponding ketone derivative,for example a compound of formula R¹COR⁸, such as(2-acetyl-5-thien-3-yl)thiophene, with tosylmethylisocyanide andpotassium t-butoxide in dimethyl ether.

Compounds of formula I can be prepared as described in Scheme II below.The reagents and starting materials are readily available to one ofordinary skill in the art. All the substituents, unless otherwisespecified are previously defined.

In Scheme II, the compound of formula II is converted to the compound offormula I under conditions well known in the art. For example, standardconditions recognized by one of ordinary skill in the art are describedby T. W. Green, “Protective Groups in Organic Synthesis,” John Wiley &Sons (1981) pages 223-264. For example, the compound of formula II isdissolved in a suitable organic solvent, such as acetonitrile andtreated with a catalytic amount of dimethylaminopyridine (DMAP). Thesolution is treated with an equivalent of an anhydride of structure (1)or chloroformate of structure (2);

wherein R^(b) represents (1-6C)alkyl, aryl, (1-6C)alkylaryl,(1-6C)alkylNH(1-6C)alkyl, (1-6C)alkylN(1-6C)alkyl₂, and(1-6C)alkylNR^(e)R^(f) wherein R^(e) and R^(f) together with thenitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl oroctahydroazocinyl group, and R^(c) represents (1-6C)alkyl, aryl, or(1-6C)alkylaryl. Examples of anhydrides (1) include but are not limitedto acetic anhydride, propionic anhydride, butyric anhydride,trimethylacetic anhydride, isobutyric anhydride, valeric anhydride,hexanoic anhydride, benzoic anhydride, 4-anisic anhydride, o-toluicanhydride, m-toluic anhydride, p-chlorobenzoic anhydride, 4-bromobenzoicanhydride, 1-naphthylacetic anhydride, and the like. Examples ofchloroformates (2) include but are not limited to methyl chloroformate,ethyl chloroformate, propyl chloroformate, butyl chloroformate, isobutylchloroformate, pentyl chloroformate, hexyl chloroformate, benzylchloroformate, phenyl chloroformate, 4-chlorophenyl chloroformate,4-nitrophenyl chloroformate, 2-nitrophenyl chloroformate, 4-nitrobenzylchloroformate, p-tolyl chloroformate, 4-bromophenyl chloroformate,4-fluorophenyl chloroformate, 4-methylphenyl chloroformate, 2-naphthylchloroformate, (((N,N-dimethyl)amino)ethyl)chloroformate, morpholinoethylchloroformate, and the like. The reaction mixture is stirred at atemperature of about −78° C. to about 100° C. for about one hour toabout 48 hours and the product is then isolated and purified usingstandard isolation and purification techniques. For example, thereaction is concentrated under vacuum, diluted with a suitable organicsolvent, such as ethyl acetate, rinsed with saturated sodiumbicarbonate, water, brine, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. The crude product can then bepurified by flash chromatography on silica gel with a suitable eluent,such as ethyl acetate/hexane to provide the purified compound of formulaI.

By way of further example, an equivalent of pivaloyloxymethyl iodide orpivaloyloxymethyl chloride is combined with the compound of formula IIin a suitable organic solvent, such as acetonitrile in the presence ofan equivalent of a suitable base, such as potassium carbonate. Thereaction is stirred at a temperature of about 0° C. to room temperaturefor 2 to 6 hours. The product is then isolated and purified bytechniques well known in the art, such as extraction techniques andchromatography.

Alternatively, in Scheme II, the compound of formula II is alkylatedunder standard conditions well known in the art with a compound ofstructure (3);

Hal—R^(d)  (3)

wherein Hal represents Cl, Br or I, and R^(d) represents (1-6C)alkyl.For example, the compound of formula II is dissolved in a suitableorganic solvent, such as tetrahydrofuran and treated with an equivalentof a suitable base, such as sodium bis(trimethylsilyl)amide. Thereaction mixture is then treated with about 1.0 to about 1.1 equivalentsof compound (3), such as iodomethane. The reaction is stirred at atemperature of about 0° C. to about 100° C. for about one hour to about48 hours. The product is then isolated by procedures well known in theart, such as extraction techniques and chromatography. For example, thereaction is diluted with a suitable organic solvent, such as ethylacetate, washed with water, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. The crude product is thenpurified by flash chromatography on silica gel with a suitable eluent,such as ethyl acetate/hexane to provide the purified compound of formulaI.

It further understood by one of ordinary skill in the art that thereaction sequence of placing the R^(a) group on the sulfonamide nitrogenin the last step, may be modified by placing the R^(a) group on thesulfonamide nitrogen following the reaction described in Scheme I andprior to the previously described further derivatization of formula II,such as when R¹ represents a 4-bromophenyl group.

The ability of compounds of formula I to potentiate glutamatereceptor-mediated response may be determined using fluorescent calciumindicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and bymeasuring glutamate-evoked efflux of calcium into GluR4 transfectedHEK293 cells, as described in more detail below.

In one test, 96 well plates containing confluent monolayers of HEK cellsstably expressing human GluR4B (obtained as described in European PatentApplication Publication Number EP-A1-583917) are prepared. The tissueculture medium in the wells is then discarded, and the wells are eachwashed once with 200 μl of buffer (glucose, 10 mM, sodium chloride, 138mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calciumchloride, 5 mM, N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid],10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutesin the dark with 20 μM Fluo3-AM dye (obtained from Molecular ProbesInc., Eugene, Oreg.) in buffer in each well. After the incubation, eachwell is washed once with 100 μl buffer, 200 μl of buffer is added andthe plates are incubated for 30 minutes.

Solutions for use in the test are also prepared as follows. 30 μM, 10μM, 3 μM and 1 μM dilutions of test compound are prepared using bufferfrom a 10 mM solution of test compound in DMSO. 100 μM cyclothiazidesolution is prepared by adding 3 μl of 100 mM cyclothiazide to 3 ml ofbuffer. Control buffer solution is prepared by adding 1.5 μl DMSO to498.5 μl of buffer.

Each test is then performed as follows. 200 μl of control buffer in eachwell is discarded and replaced with 45 μl of control buffer solution. Abaseline fluorescent measurement is taken using a FLUOROSKAN IIfluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, aDivision of Life Sciences International Plc). The buffer is then removedand replaced with 45 μl of buffer and 45 μl of test compound in bufferin appropriate wells. A second fluorescent reading is taken after 5minutes incubation. 15 μl of 400 μM glutamate solution is then added toeach well (final glutamate concentration 100 μM), and a third reading istaken. The activities of test compounds and cyclothiazide solutions aredetermined by subtracting the second from the third reading(fluorescence due to addition of glutamate in the presence or absence oftest compound or cyclothiazide) and are expressed relative to enhancefluorescence produced by 100 μM cyclothiazide.

In another test, HEK293 cells stably expressing human GluR4 (obtained asdescribed in European Patent Application Publication No. EP-A1-0583917)are used in the electro-physiological characterization of AMPA receptorpotentiators. The extracellular recording solution contains (in mM): 140NaCl, 5 KCl, 10 HEPES, 1 MgCl₂, 2 CaCl₂, 10 glucose, pH=7.4 with NaOH,295 mOsm kg-1. The intracellular recording solution contains (in mM):140 CsCl, 1 MgCl₂, 10 HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH=7.2 with CsOH,295 mOsm kg-1. With these solutions, recording pipettes have aresistance of 2-3 MΩ. Using the whole-cell voltage clamp technique(Hamill et al.(1981)Pflügers Arch., 391: 85-100), cells arevoltage-clamped at −60 mV and control current responses to 1 mMglutamate are evoked. Responses to 1 mM glutamate are then determined inthe presence of test compound. Compounds are deemed active in this testif, at a test concentration of 10 μM, they produce a greater than 30%increase in the value of the current evoked by 1 mM glutamate.

In order to determine the potency of test compounds, the concentrationof the test compound, both in the bathing solution and co-applied withglutamate, is increased in half log units until the maximum effect wasseen. Data collected in this manner are fit to the Hill equation,yielding an EC₅₀ value, indicative of the potency of the test compound.Reversibility of test compound activity is determined by assessingcontrol glutamate 1 mM responses. Once the control responses to theglutamate challenge are re-established, the potentiation of theseresponses by 100 μM cyclothiazide is determined by its inclusion in boththe bathing solution and the glutamate-containing solution. In thismanner, the efficacy of the test compound relative to that ofcyclothiazide can be determined.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinabove and apharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions are prepared by known procedures usingwell-known and readily available ingredients. In making the compositionsof the present invention, the active ingredient will usually be mixedwith a carrier, or diluted by a carrier, or enclosed within a carrier,and may be in the form of a capsule, sachet, paper, or other container.When the carrier serves as a diluent, it may be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. The compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols, ointments containing, forexample, up to 10% by weight of active compound, soft and hard gelatincapsules, suppositories, sterile injectable solutions, and sterilepackaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia,calcium phosphate, alginates, tragcanth, gelatin, calcium silicate,micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifylng and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 mg to about 500 mg, more preferably about5 mg to about 300 mg (for example 25 mg) of the active ingredient. Theterm “unit dosage form” refers to a physically discrete unit suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier, diluent, or excipient. The following formulationexamples are illustrative only and are not intended to limit the scopeof the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantify (mg/capsule) Active Ingredient 250 Starch, dried 200 MagnesiumStearate  10 Total 460

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Tablets each containing 60 mg of active ingredient are made as follows:

Quantity (mg/tablet) Active Ingredient 60 Starch 45 MicrocrystallineCellulose 35 Polyvinylpyrrolidone 4 Sodium Carboxymethyl Starch 4.5Magnesium Stearate 0.5 Talc 1 Total 150

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

As used herein the term “patient” refers to a mammal, such as a mouse,guinea pig, rat, dog or human. It is understood that the preferredpatient is a human.

As used herein the term “effective amount” refers to the amount or doseof the compound which provides the desired effect in the patient underdiagnosis or treatment.

The particular dose of compound administered according to this inventionwill of course be determined by the particular circumstances surroundingthe case, including the compound administered, the route ofadministration, the particular condition being treated, and similarconsiderations. The compounds can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, or intranasal routes. Alternatively, the compound may beadministered by continuous infusion. A typical daily dose will containfrom about 0.01 mg/kg to about 100 mg/kg of the active compound of thisinvention. Preferably, daily doses will be about 0.05 mg/kg to about 50mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

The following examples represent typical syntheses of starting materialsfor the compounds of formula I, and of compounds of formula I asdescribed generally above. These examples are illustrative only and arenot intended to limit the invention in any way. The reagents andstarting materials are readily available to one of ordinary skill in theart. As used herein, the following terms have the meanings indicated:“Eq” refers to equivalents; “g” refers to grams; “mg” refers tomilligrams; “L” refers to liters; “mL” refers to milliliters; “μL”refers to microliters; “mol” refers to moles; “mmol” refers tomillimoles; “psi” refers to pounds per square inch; “° C.” refers todegrees Celsius; “TLC” refers to thin layer chromatography; “HPLC”refers to high performance liquid chromatography; “R_(f)” refers toretention factor; “R_(t)” refers to retention time; “δ” refers to partper million down-field from tetramethylsilane; “THF” refers totetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “DMSO” refers tomethyl sulfoxide; “EtOAc” refers to ethyl acetate; and “LDA” refers tolithium diisopropylamide.

Preparation 1 2-(4-Bromophenyl)Propionitrile

A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate washeated to 180° C. in a sealed vessel for 16 hours. The solution was thencooled, diluted with 200 ml of ethyl acetate and washed once with 100 mlwater, once with 100 ml of 10% aqueous sodium bisulfate and once with100 ml brine. The organic portion was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was distilled under vacuum through ashort path distillation apparatus to afford 40.3 g (85%) of the titlecompound.

Preparation 2 2-(4-Bromophenyl)propylamine hydrochloride

To a solution of 35.2 g (167.6 mmol) of material from Preparation 1under reflux in 35.0 mL of tetrahydrofuran was added 18.4 ml (184.3mmol) of 10M borane-dimethyl-sulfide slowly via a syringe. The solutionwas heated under reflux for an additional 1 hour after the addition wascomplete. The solution was cooled to ambient temperature and a saturatedsolution of hydrogen chloride in methanol was added slowly until pH 2was achieved. The resulting slurry was concentrated in vacuo. Theresidue was dissolved in methanol and concentrated in vacuo twice. Theresulting solid was suspended in ethyl ether, filtered, rinsed withethyl ether and dried in vacuo to afford 31.2 g (74%) of the titlecompound.

Preparation 3 2-Fluorobenzeneboronic Acid

A solution of 50 g (285.6 mmol) of 2-fluorobromobenzene in 400 mL oftetrahydrofuran was cooled to −78° C. and 200 mL (320.0 mmol) of 1.6Mn-Butyllithium was added via a cannula. The mixture was stirred at −78°C. for 60 minutes, then 98.9 mL (428.4 mmol) of triisopropyl borate wasadded via a cannula and stirring was continued for 60 minutes. Thecooling bath was removed and the mixture was stirred at ambienttemperature for 1.5 hours, then 150 mL of 6N hydrochloric acid was addedand stirring was continued for 1.5 hours. To the mixture was added 100mL of brine, and then the organic layer was separated and the aqueouslayer was extracted three times with 30 mL each of ether. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.The residue was recrystallized from water to afford 25.2 g (63%) of thetitle compound.

Preparation 4 2-(4-bromophenyl)-N-(t-butoxycarbonyl)propylamine

To a solution of 11.8 g (55.0 mmol) of material from Preparation 2 in100 mL of chloroform and 100 mL of saturated sodium bicarbonate wasadded 12.0 g (55.0 mmol) of di-tert-butyl dicarbonate. The solution wasstirred at ambient temperature for 1 hour. The organic layer wasseparated and the aqueous layer was extracted three times with 30 mLeach of chloroform. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo to afford 16.5 g (95%) of the titlecompound.

Preparation 52-(4-(2-fluorophenyl)phenyl)-N-(t-butoxycarbonyl)propylamine

To a degassed solution of 12.5 g (39.8 mmol) of material fromPreparation 4, 6.7 g (47.7 mmol) of material from Preparation 3 and 8.2g (59.7 mmol) of potassium carbonate in 140 mL of toluene was added 2.3g (1.9 mmol) of tetrakis (triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 hours. The mixture was then cooled toambient temperature and 300 mL of water and 150 mL of ether were added.The organic layer was separated and the aqueous layer was extractedthree times with 50 mL each of ethyl acetate. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (500 g of silica gel, 10% ethyl acetate/hexane) of theresidue afforded 9.3 g (71%) of the title compound.

Preparation 6 2-(4-(2-fluorophenyl)phenyl)propylamine

A solution of 9.3 g of material from Preparation 5 in 100 mL 20%trifluoroacetic acid/dichloromethane was stirred at ambient temperaturefor 2 hours. The mixture was concentrated in vacuo to afford 11.7 g ofmaterial. The material was dissolved in 100 mL of ether and washed twicewith 50 mL of 1N sodium hydroxide. The organic layer was concentrated invacuo to afford 5.48 g (85%) of the title compound.

Preparation 7 2-(4-Isopropylphenyl)propionitrile

In a 250 ml flask, 4-isopropylphenylacetonitrile 8.00 g (50.2 mmol) wasdissolved in tetrahydrofuran (150 ml) under a nitrogen atmosphere. Thesolution was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1Min tetrahydrofuran, 52.8 ml (52.8 mmol) added. The resulting mixture wasstirred at −78° C. for 1 hour. To this reaction mixture was addediodomethane 3.29 ml (52.8 mmol). The resulting mixture was slowlyallowed to warm to ambient temperature over 16 hours then quenched with0.2M hydrochloric acid and extracted twice with diethyl ether. Theorganic fractions were combined, dried (MgSO₄) and concentrated undervacuo. Chromatography (SiO₂, 20% ethyl acetate/hexanes) gave 6.32 g(73%) of the title compound.

Field Desorption Mass Spectrum: M=173.

Analysis for C₁₂H₁₅N: Theory: C, 83.19; H, 8.73; N, 8.08. Found: C,82.93; H, 8.57, N, 8.02.

Preparation 8 2-(4-Isopropylphenyl)propylamine hydrochloride

In a 100 ml flask, fitted with a condenser, 2-(4-isopropylphenyl)propionitrile 1.90 g (11.0 mmol) was dissolved in tetrahydrofuran (70ml) under a nitrogen atmosphere. Borane-methyl sulfide complex(10.0-10.2 M in tetrahydrofuran, 1.20 ml, 12.1 mmol) was added to thesolution and the mixture heated to reflux for 3 hours. The solution wascooled to ambient temperature and a saturated solution of hydrochloricacid in methanol added slowly until a white precipitate formed. Thesolvent was removed in vacuo and the resulting white solid triturated(×4) with diethyl ether. Drying under vacuo gave 1.76 g (73%) of thetitle compound.

Preparation 9 2-(4-Methoxyphenyl)propionitrile

Following the method of Preparation 7, but using4-methoxyphenylacetonitrile 5.00 g (34.0 mmol), 6.32 g of the titlecompound was obtained.

Field Desorption Mass Spectrum: M=161.

Analysis for C₁₀H₁₁NO: Theory: C, 74.51; H, 6.88; N, 8.69. Found: C,74.34; H, 6.67; N, 8.93.

Preparation 10 2-(4-Methoxyphenyl)propylamine hydrochloride

Following the method of Preparation 8, but using the product ofPreparation 9, 2.75 g (17.1 mmol), 2.77 g (81%) of the title compoundwas obtained.

Analysis for C₁₀H₁₆CINO: Theory: C, 59.55; H, 8.00; N, 6.94. Found: C,59.33; H, 7.89; N, 6.71.

Preparation 11 Methyl 2-(4-t-butylphenyl)propanoate

23.3 mL of lithium bis(trimethylsilyl)amide (1.0 M, 23 mmols) was addeddropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100mL of dry THF at −78° C. while stirring under nitrogen. The mixture wasstirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyliodide was added dropwise and the solution was stirred for an additional1 hour at −78° C. The mixture was poured into 200 mL of H₂O and thedesired product was extracted with 500 mL diethyl ether. The organiclayer was backwashed once with 500 mL H₂O, dried over K₂CO₃, andconcentrated under reduced pressure to yield 5.12 of a dark oil. The oilwas purified via silica gel chromatography eluting with a solventgradient of hexane to hexane/ethyl acetate 19:1. The fractionscontaining the desired product were combined and concentrated underreduced pressure to yield the title compound 2.65 g (53%).

Mass Spectrum: M=220.

Preparation 12 Methyl 2-(4-t-butylphenyl)butanoate

4 g (19 mmol) of methyl 4-tert-butylphenylacetate, 19.5 mL (1.0 M, 19mmol) of lithium bis(trimethylsilyl)amide and 3.12 g (20 mmol) of ethyliodide were reacted as described in Preparation 11 to yield 5.13 g of abrown oil. Chromatography, eluting with a gradient solvent of hexane tohexane/ethyl acetate 19:1 gave the title compound 2.35 g (53%).

Mass Spectrum: M=234.

Preparation 13 Methyl 2-(4-t-butylphenyl)-2-methylpropanoate

4.75 g (23 mmol) of methyl 4-tert-butylphenylacetate, 46.6 mL (1.0 M, 46mmol) of lithium bis(trimethylsilyl)amide, and 6.80 g (48 mmols) ofmethyl iodide were reacted as described in Preparation 11 to yield 4.73g of a crude oil. Chromatography, eluting with a solvent gradient ofhexane to hexane/ethyl acetate 19:1, gave the title compound 2.0 g(37%).

Mass Spectrum: M=234.

Preparation 14 Ethyl 2-(2-naphthyl)propanoate

5 g (23 mmol) of ethyl 2-naphthylacetate, 23.3 mL (1.0 M, 23 mmol) oflithium bis(trimethylsilyl)amide, and 1.5 mL (2 4 mmol) of methyl iodidewere reacted as described in Preparation 11 to yield 5.71 g of a darkoil. Chromatography eluting with a solvent gradient of hexane tohexane/ethyl acetate 19:1 gave the title compound 2.85 g (54%).

Mass Spectrum: M=228.

Preparation 15 2-(4-t-butylphenyl)propanoic Acid

2.60 g (12 mmol) of the product of Preparation 11 and 1.75 g (42 mMol)of lithium hydroxide were placed into a tri-solvent solution oftetrahydrofuran (189 mL), CH₃OH (63 mL), and H₂O (63 mL) and stirred atambient temperature for 16 hours. The mixture was then concentratedunder reduced pressure and the resulting white solid was taken into 200mL 1N HCl and the desired product was extracted with 250 mL ethylacetate. The organic layer was concentrated under reduced pressure togive the title compound 1.21 g (49%).

Mass Spectrum: M=206.

Preparation 16 2-(4-t-butylphenyl)butanoic Acid

The title compound (2.14 g) was prepared by the method of Preparation15, starting from the product of Preparation 12, and recrystallized fromhexane.

Mass Spectrum: M=220.

Preparation 17 2-(4-t-butylphenyl)-2-methylpropanoic Acid

The title compound (1.75 g) was prepared by the method of Preparation 15starting from the product of Preparation 13, and recrystallized fromhexane.

Mass Spectrum: M=220.

Preparation 18 2-(2-Naphthyl)propanoic Acid

The title compound (3.81 g) was prepared by the method of Preparation 15starting from the product of Preparation 14, and recrystallized fromhexane/ethyl acetate 9:1.

Mass Spectrum: M=214.

Preparation 19 2-(4-t-butylphenyl)propionamide

900 mg (4.4 mmol) of the product of Preparation 15 was added portionwiseto oxalyl chloride (10 mL) at ambient temperature under N₂ followed byCH₂Cl₂ (10 mL). Initiation of the reaction was accomplished by theaddition of one drop of DMF. An evolution of gas appeared and thereaction was stirred at ambient temperature for 2 hours. The solutionwas concentrated under reduced pressure to yield an oil. Dioxane (10 mL)was added for solubility and while stirring at ambient temperature, 28%ammonium hydroxide (10 mL) was added and the reaction was stirred for 16hours. The solution was then concentrated under reduced pressure toyield a white solid. This solid was taken into 50 mL ethyl acetate,backwashed once with 50 mL H₂O, dried over K₂CO₃, and concentrated underreduced pressure to yield 770 mg of a solid. Recrystallization fromhexane/ethyl acetate 1:1 gave the title compound 555 mg (61%).

Mass Spectrum: M=205.

Preparation 20 2-(4-t-butylphenyl)butanamide

The title compound was prepared by the method of Preparation 19,starting from the product of Preparation 16. Purification was achievedby silica gel chromatography (Chromatotron-2000 micron rotor) elutingwith a solvent of hexane/ethyl acetate 1:1 to yield 471 mg (60%).

Mass Spectrum: M=219.

Preparation 21 2-(4-t-butylphenyl)-2-methlypronpionamide

The title compound was prepared following the method of Preparation 19,starting from the product of Preparation 17. The crude product wastriturated with a solution of hexane/-ethyl acetate 19:1 for ½ hour andfiltered to yield 1.16 g of a white solid. Subsequent recrystallizationfrom ethyl acetate/ethanol 1:1 gave an 80% recovery as platelets.

Mass Spectrum: M=219.

Preparation 22 2-(2-Naphthyl)propionamide

The title compound was prepared following the method of Preparation 19,starting from the product of Preparation 18. Recrystallization fromhexane/ethyl acetate 1:1 yielded 1.65 g (90%).

Mass Spectrum: M=199.

Preparation 23 2-(4-t-butylphenyl)propylamine

25 mL of Borane-tetrahydrofuran complex (1.0 M, 0.025 Mol) was added viaa syringe to 1.10 g (5.4 mmol) of the product of Preparation 19 (60 mL)at ambient temperature under N₂. The mixture was then heated at 60°-65°C. for 16 hours. A saturated HCl/methanol solution (5 mL) was then addedvia a syringe at ambient temperature with severe foaming and thesolution was then concentrated under reduced pressure. The resultingwhite solid was taken into 100 mL 1 N NaOH and the liberated free aminewas extracted once with 200 ml diethyl ether. The organic layer wasbackwashed once with 200 mL H₂O, dried over K₂CO₃, and concentratedunder reduced pressure to yield 1.21 g of a brown oil. Chromatography(Chromatotron-2000 micron rotor) eluting with a gradient solvent ofethyl acetate/MeOH 9:1 to MeOH gave 856 mg (83%).

Mass Spectrum: M=191.

Preparation 24 2-(4-t-butylphenyl)butylamine

The title compound 540 mg was prepared as an oil by the method ofPreparation 23, starting from the product of Preparation 20.

Mass Spectrum: M=205.

Preparation 25 2-(4-t-butylphenyl)-2-methylpropylamine

The title compound 428 mg (42%) was prepared following the method ofPreparation 23, starting from the product of Preparation 21, and usingmethanol as the chromatography solvent.

Mass Spectrum: M=205.

Preparation 26 2-(2-Naphthyl)propylamine

The title compound, 450 mg (44%) was prepared as an oil following themethod of Preparation 23, starting from the product of Preparation 22,and using methanol as the chromatography solvent.

Mass Spectrum: M=185.

Preparation 27 Methyl 1-(4-t-butylphenyl)cyclopropanecarboxylate

4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mL (1.0 m, 2Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of1-bromo-2-chloroethane in 100 mL dry THF were reacted as described inPreparation 11, except that the reaction mixture was stirred for onehour at ambient temperature before work-up. This reaction yielded 4.21 gof a brown oil. This material was purified via silica gel chromatographyeluting with a gradient solvent of hexane to hexane/EtOAc 19:1 to yieldthe title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C.Calculated for C₁₅H₂₀O₂: Theory: C, 77.37; H, 8.81 Found: C, 77.54; H,8.68.

Preparation 28 1-(4-t-butylphenyl)cyclopropanecarboxylic acid

1 g (4.3 mmol) of the product of Preparation 27 and 650 mg (15.5 mmol)of lithium hydroxide were placed in a tri-solvent solution of THF (66mL), methanol (22 mL), and H₂O (22 mL) and reacted as described inPreparation 15 to yield 840 mg of a solid. This material was purifiedvia silica gel chromatography eluting with hexane/EtOAc 1:1 as a solventto yield the title compound, 600 mg, (64%) as a white solid. m.p.dec>150° C. Calculated for C₁₄H₁₈O₂: Theory: C, 77.03; H, 8.31 Found: C,77.08; H, 8.02.

Preparation 29 1-(4-t-butylphenyl)cyclopropanecarboxamide

580 mg. (2.7 mmol) of the product of Preparation 27, oxalyl chloride (10mL), methylene chloride (10 mL) and one drop DMF were reacted asdescribed in Preparation 19 to yield 573 mg of the crude acid chloride.Amide conversion was accomplished with 28% ammonium hydroxide (10 mL)and dioxane (10 mL) as described in Preparation 27 to yield 590 mg of asolid. Trituration in hexane/EtOAc. 19:1 and subsequent filtrationyielded 510 mg (87%) of the title compound as a white solid. m.p.178°-180° C. Calculated for C₁₄ H₁₉NO: Theory: C, 77.38; H, 8.81; N,6.45 Found: C, 77.53; H, 8.77; N, 6.39.

Preparation 30 1-(4-t-butylphenyl)cyclopropylmethylamine

7 mL of Borane-tetrahydrofuran complex (1.0 M, 7 mmol) and 500 mg (2.3mmol) of the product of Preparation 29 in THF (50 mL) were reacted asdescribed in Preparation 23 to yield 510 mg of an oil. Purification wasachieved via silica gel chromatography eluting with a gradient solventof EtOAc/methanol 9:1 to methanol to yield 222 mg (47%) as a solid, m.p.39°-41° C. Calculated for C₁₄H₂₁N: Theory C, 82.70; H, 10.41; N, 6.89Found: C, 81.36; H, 10.13; N, 7.24.

Preparation 31 2-(4-Bromophenyl)propylamine hydrochloride

To a −15° C. solution of 50.0 g (251.2 mmol) of 4-bromo-acetophenone and49.0 g (251.2 mmol) of tosylmethyl iso-cyanide in 800 mL of drydimethoxyethane was added a hot solution of 50.7 g (452.2 mmol) ofpotassium tert-butoxide in 230 mL of tert-butyl alcohol dropwise at arate to maintain the temperature below 0° C. The reaction was stirred at−5° C. for 45 min after addition was complete. The cooling bath wasremoved and the reaction stirred for 2.5 h more. The mixture wasconcentrated in vacuo to a volume of 200 mL and diluted with 500 mL ofwater. The aqueous mixture was extracted four times with diethyl ether,and the combined organic portions were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in 55 mL oftetrahydrofuran and heated to reflux. To the refluxing solution wasadded slowly dropwise 27.6 mL (276.3 mmol) of 10.0 Mborane-dimethylsulfide complex. Refluxing was continued for 20 min afteraddition was complete. The mixture was cooled to ambient temperature andmethanol saturated with hydrogen chloride was added very slowly until pH2 was achieved. The mixture was concentrated in vacuo and the residuewas dissolved in methanol and concentrated in vacuo again. The solidresidue was suspended in 125 mL of ethanol, filtered, rinsed withethanol then diethyl ether. The white solid was dried in vacuo to afford25.4 g (40%) of the title compound. The filtrate was concentrated invacuo and suspended in diethyl ether. The solid was filtered, rinsedwith diethyl ether and dried in vacuo to afford another 15.6 g (25%) ofthe title compound.

Preparation 32 2-(4-Methylphenyl)propionitrile

The title compound was prepared from 4-methylphenyl-acetonitrile asdescribed in Preparation 7.

Analysis for C₁₀H₁₁N: Theory: C, 82.72; H, 7.64; N, 9.65. Found: C,82.75; H, 7.42; N, 9.94.

Preparation 33 2-(4-Methylphenyl)propylamine hydrochloride

The title compound was prepared from the product of Preparation 32 asdescribed in Preparation 8.

Field Desorption Mass Spectrum: M=150 (M-HCl)

Preparation 34 2-(4-Benzyloxyphenyl)propionitrile

4-Hydroxyphenylacetonitrile (15.3 g, 114.9 mmol) was dissolved indimethylformamide (120 ml) and to this was added potassium carbonate(23.78 g, 172.4 mmol), benzyl bromide (20.64 g, 120.6 mmol) andpotassium iodide (3.81 g, 30.0 mmol). The solution was stirred atambient temperature for 6 hours after which water was added.4-Benzyloxyphenyl-acetonitrile precipitated out of solution. Thesuspension was filtered and the precipitate washed with water (3×).Yield 24.8 g (97%) as yellow crystals. The title product was preparedfrom 4-benzyloxyphenyl-acetonitrile as described in Preparation 7. Yield76%.

Field Desorption Mass Spectrum: M=237.2.

Analysis for C₁₆H₁₅NO: Theory: C, 80.98; H, 6.37; N, 5.90. Found: C,80.93; H, 6.46; N, 6.11.

Preparation 35 2-(4-Benzyloxyphenyl)propylamine hydrochloride

The title compound was prepared from the product of Preparation 34 asdescribed in Preparation 2.

Analysis for C₁₆H₂₀CINO: Theory: C, 59.55; H, 8.00; N, 6.94. Found: C,59.33; H, 7.89; N, 6.71.

Preparation 36 N-t-butoxycarbonyl-N-(2-(4-hydroxyphenyl)propyl)2-propanesulfonamide

The product of Example 40 (7.6 g, 23.8 mmol) was dissolved indichloromethane (100 ml) and to this mixture was added di-tert-butyldicarbonate (5.71 g, 26.2 mmol) and 4-dimethylaminopyridine (1.45 g,11.9 mmol). The reaction was stirred at ambient temperature for 1 hour.The reaction was washed with a saturated aqueous solution of sodiumhydrogen sulfate and brine. The organic fraction was dried overmagnesium sulfate and concentrated under vacuo. The protectedsulfonamide (9.00 g, 21.0 mmol) was dissolved in ethyl acetate: H₂O(5:1) and ammonium formate (2.0 g, 31.5 mmol) added to the mixture. Thenpalladium on carbon (10%) (0.9 g) was added to the reaction and this wasstirred at ambient temperature for 6 hours. The suspension was filteredthrough celite and the resulting solution concentrated in vacuo to give5.51 g (78%) of title product.

Field Desorption Mass Spectrum: M=329.1.

Analysis for C₁₅H₂₃NO₅S: Theory: C, 54.69; H, 7.04; N, 4.25. Found: C,53.70; H, 7.72; N, 4.04.

Preparation 37 2-(4-bromophenyl)-1-nitro-1-methylethylene

A solution of 30.0 g (162 mmol) of 4-bromobenzaldehyde, 116 mL (1.6mole) of nitroethane, and 37.5 g (486 mmol) of ammonium acetate in 200mL of toluene was heated under a Dean and Stark trap for 18 hours. Themixture was then cooled to 80° C., 1 mL of concentrated sulfuric acidwas added, and the mixture was stirred at 80° C. for 2 hours. Themixture was then cooled to ambient temperature and washed with 200 mL ofbrine. The organic layer was separated and the aqueous layer wasextracted three times with 60 mL of diethyl ether. The combined organicswere dried (MgSO₄), filtered and concentrated in vacuo. The residue wasrecrystallized from methanol to afford 18.7 g (47%) of the titlecompound.

Preparation 38 2-(4-bromophenyl)-1-nitro-1-methylethane

A suspension of 1.3 g (33.9 mmol) of lithium aluminum hydride in 55 mLof tetrahydrofuran (THF) was cooled to 0° C. A solution of 4.1 g (16.9mmol) of material from Preparation 37 in 5 mL of THF was added dropwise.1.3 mL of water, 1.3 mL of 1M sodium hydroxide and 4.0 mL of water wereadded in sequence. The mixture was filtered through celite and rinsedwith dichloromethane. The organics were concentrated in vacuo to afford3.0 g of the title compound (83%).

Preparation 39 N-2-(4-bromophenyl)propyl 2-proanesulfonamide

A solution of 15.0 g (59.9 mmol) of the material from Preparation 31 and18.4 mL (131.8 mmol) of triethylamine in 150 mL of dichloromethane wasstirred 20 min at room temperature, then cooled to 0° C. and treateddropwise over 5 min with 8.1 mL (71.9 mmol) of 2-propylsulfonyl chloridein 10 mL of dichloromethane. After stirring overnight at roomtemperature, the reaction was washed once with 200 mL of 10% aqueoussodium bisulfate, the layers separated and the aqueous layer extractedtwice with 100 mL each of dichloromethane. The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(500 g of silica gel, 30% ethyl acetate/ hexane) of the residue afforded11.0 g (57%) of the title compound.

Preparation 40 N-2-(4-tri-n-butylstannylphenyl)popyl2-propanesulfonamide

To a degassed solution of 4.8 g (15.1 mmol) of material from Preparation39, 2.1 mL (15.1 mmol) of triethylamine and 8.0 mL (15.9 mmol) ofhexabutyiditin in 35 mL of toluene add 0.9 g (0.8 mmol) of tetrakis(triphenylphosphine) palladium (0). The mixture was heated to 100° C.for 16 hours, cooled to room temperature and diluted with 35 mL of ethylacetate. The mixture was washed with 50 mL of 10% aqueous sodiumbisulfate, the organic layer was separated and the aqueous layer wasextracted two times with 50 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (350 g of silica gel, 20% ethyl acetate/hexane) of theresidue afforded 3.5 g (44%) of the title compound as a clear, colorlessoil.

Analysis calculated for C₂₄H₄₅NO₂SSn: %C, 54.35; %H, 8.55; %N, 2.64.Found: %C, 54.41; %H, 8.16; %N, 2.74.

Mass Spectrum: M=530.

Preparation 41 2-(4-bromophenyl)-N-(t-butoxycarbonyl)ethylamine

To a room temperature solution of 10.0 g (50.0 mmol) of4-bromophenethylamine and 11.0 g (50.0 mmol) of di-tert-butyldicarbonate in 100 mL of chloroform was added 100 mL of saturatedaqueous sodium bicarbonate. The mixture was stirred at room temperaturefor 1.5 hours and diluted with 100 mL of water. The organic layer wasseparated and the aqueous layer was extracted two times with 100 mL eachof chloroform. The combined organics were washed once with 100 mL of 10%aqueous sodium bisulfate, dried (NaSO₄), filtered and concentrated invacuo to afford 14.6 g (97%).

Mass Spectrum: M+1=301.

Preparation 42 4-cyanophenylboronic acid

A solution of 10.0 g (54.9 mmol) of 4-bromobenzonitrile in 100 mL oftetrahydrofuran was cooled to −85° C. whereupon 36.0 mL (57.6 mmol) of1.6 M solution of n-butyllithium in hexane was added. The mixture wasstirred for five minutes and 19.0 mL (82.4 mmol) of triisopropylboratewas added. The mixture was stirred at −85° C. for 30 minutes then warmedto ambient temperature over one hour. To the mixture was added 35 mL of5 N hydrochloric acid and stirring was continued for 2.5 hours. Themixture was diluted with 100 mL of saturated aqueous sodium chloride andextracted three times with 100 mL each of ethyl ether. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was recrystallized from water and filtered to afford 2.0 g (25%)of the title compound.

Preparation 43 N-2-(4-formylphenyl)propyl 2-propanesulfonamide

A solution of 4.6 g (14.5 mmol) of material from Preparation 39 in 50 mLof tetrahydrofuran was cooled to −85° C. and 19 mL (30.5 mmol) of 1.6Mn-Butyllithium was added via syringe. The mixture was stirred at −85° C.for 30 min then 2.2 mL (29.0 mmol)of N,N-dimethylformamide was added viasyringe and stirring was continued for 30 min. The mixture was stirredat 0° C. for 30 min and then 100 mL of brine and 50 mL of ether wasadded. The organic layer was separated and the aqueous layer wasextracted three times with 20 mL each of ether. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (200 g of silica gel, 40% ethyl acetate/hexane) of theresidue afforded 2.2 g (56%) of the title compound.

Preparation 44N-2-(4-(4-(1-hydroxy-2-(N-(t-butoxycarbonyl)-methylsulfonamido)ethyl)phenyl)phenyl)propyl 2-propanesulfonamide

A. N-(t-butoxycarbonyl)methanesulfonamide: To a solution of 15.0 g(157.7 mmol) of methanesulfonamide, 17.6 g (173.5 mmol) of triethylamineand 1.9 g (15.8 mmol) of 4-dimethylaminopyridine in 200 mL ofdichloromethane was added of 37.9 g (173.5 mmol) ofdi-t-butyldicarbonate in 200 mL of dichloromethane over ten minutes. Themixture was stirred at ambient temperature for 2.25 hours andconcentrated in vacuo. The residue was dissolved in 250 mL of ethylacetate and washed once with 200 mL of 1 N hydrochloric acid, once with100 mL of water and once with 100 mL of saturated aqueous sodiumchloride. The organic layer was dried (MgSO₄), filtered and concentratedin vacuo. The residue was suspended in 100 mL of hexane, filtered anddried in vacuo to afford 26.1 g (85%) of the title compound.

Analysis calculated for C₇H₁₃NO₄S: %C, 36.91; %H, 6.71; %N, 7.17. Found:%C, 36.97; %H, 6.79; %N, 7.04.

Mass Spectrum: M+1=196.

B. N-(4-bromophenyl)carbonylmethyl-N-t-butoxycarbonylmethane-sulfonamide: A solution of 1.0 g (5.1 mmol) of material fromStep A, 1.4 g (5.1 mmol) of 2,4′-dibromoacetophenone and 0.8 g (5.6mmol) of potassium carbonate in 25 mL of acetonitrile was stirred atambient temperature for two hours. The mixture was diluted with 25 mL ofethyl acetate and washed once with 15 mL of water. The organic layer wasseparated and the aqueous layer was extracted three times with 10 mLeach of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (50 g of silica gel,20% ethyl acetate/hexane) of the residue afforded 1.5 g (76%) of thetitle compound.

Analysis calculated for C₁₄H₁₇NBrO₅S: %C, 42.87; %H, 4.63; %N, 3.57.Found: %C, 43.11; %H, 4.66; %N, 3.37.

Mass Spectrum: M−1=391.

C. N-[2-(4-Bromophenyl)2-hydroxyethyl]-N-(t-butoxycarbonyl)methane-sulfonamide: To a solution of 2.6 g (6.7 mmol) of material fromStep B in 25 mL of ethanol was added 0.3 g (6.7 mmol) of sodiumborohydride and the mixture was stirred for 16 hours. The mixture wasconcentrated in vacuo and the residue was partitioned between 25 mL ofethyl acetate and 25 mL of water. The organic layer was separated andthe aqueous layer was extracted three times with 10 mL each of ethylacetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo to afford 2.6 g (98%) of the title compound.

Analysis calculated for C₁₄H₁₉NBrO₅S: %C, 42.65; %H, 5.11; %N, 3.55.Found: %C, 42.60; %H, 5.08; %N, 3.46.

Mass Spectrum: M=394.

D. To a degassed solution of 0.6 g (1.5 mmol) of material from Step Cand 0.8 g (1.5 mmol) of material from Preparation 40 in 5 mL of toluenewas added 0.08 g (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to reflux for 16 hours, cooled to ambienttemperature and diluted with 10 mL of ethyl acetate. The mixture waswashed once with 8 mL of saturated aqueous potassium fluoride, theorganic layer was separated and the aqueous layer was extracted fourtimes with 5 mL each of ethyl acetate. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (50 g ofsilica gel, 50% ethyl acetate/hexane) of the residue afforded 0.3 g(32%) of the title compound.

Analysis calculated for C₂₆H₃₈N₂O₇S₂. 0.05 CHCl₃: %C, 55.80; %H, 6.84;%N, 5.00. Found: %C, 55.47; %H, 6.93; %N, 4.72.

Mass Spectrum: M=554.

Preparation 45 Dibromoformaldoxime

A solution of 150 g (1.6 mole) of glyoxylic acid and 142 g (2.0 mole)ofhydroxylamine hydrochloride in 1200 mL of water was stirred for 2 days.To the mixture was added slowly 342 g (4.1 mole) of sodium bicarbonateand 1000 mL of dichloromethane. The mixture was cooled to 0° C. and asolution of 147 mL (2.8 mole) bromine in 700 mL of dichloromethane wasadded dropwise. The mixture was stirred at ambient temperature for 18 h.The organic layer was separated and the aqueous layer was extractedthree times with 300 mL each of dichloromethane. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo toafforded 93.1 g (28%) of the title compound.

Preparation 46 2-trimethylstannylthiazole

A. To a −78° C. solution of 5.0 g (58.7 mmol) of thiazole in 120 mL oftetrahydrofuran was added of 36.7 mL (58.7 mmol) of a 1.6 M solution ofn-butyllithium in hexane. The mixture was stirred for 20 minuteswhereupon 11.7 g (58.7 mmol) in 15 mL of tetrahydrofuran was addeddropwise over 15 minutes. The cooling bath was removed and the mixturewas stirred for two hours. The mixture was diluted with 100 mL of waterand extracted three times with 100 mL ethyl ether. The combined organicswere dried (MgSO₄), filtered and concentrated in vacuo. The residue wasdissolved in 50 mL of ethyl ether, filtered through silica gel andconcentrated in vacuo to afford 3.6 g (24%) of the title compound.

Preparation 47 N-2-(4-bromophenyl)ethyl 2-propanesulfonamide

To a solution of 10.0 g (50 mmol) of 4-bromophenethylamine and 7.6 mL(55 mmol) of triethylamine in 150 mL of dichloromethane was added asolution of 6.2 mL (55 mmol) of isopropylsulfonyl chloride in 40 mL ofdichloromethane dropwise. The mixture was stirred at room temperaturefor 18 h. The mixture was washed with 100 mL of 1N aqueous hydrochloricacid, the organic layer was separated and the aqueous layer extractedone time with 100 mL each of dichloromethane. The combined organics weredried (Na₂SO₄), filtered and concentrated in vacuo to afford 6.7 g (44%)of the title compound.

Preparation 48 N-2-(4-(tri-n-butylstannyl)phenyl)ethyl2-propanesulfonamide

To a solution of 5.0 g (16.3 mmol) of material from Preparation 47, 9.9g (17.1 mmol) of bis-tri-n-butylstannyl and 2.3 mL (16.3 mmol) oftriethylamine in 55 mL of toluene was added 0.9 g (0.8 mmol) oftetrakis(triphenylphosphine) palladium(0). The mixture was heated at100° C. for 18 h. The mixture was cooled to room temperature and 55 mLof was 10% aqueous sodium bisulfate added. The organic layer wasseparated and the aqueous layer was extracted two times with 20 mL eachof ether. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (400 g of silica gel, 25% ethylacetate/hexane) of the residue afforded 3.5 g (42%) of the titlecompound.

Preparation 49 4-(4-Bromophenyl)-1,1-dioxotetrahydro-1,2-thiazine

A. Ethyl 4-bromophenylacetate: A solution of 25.0 g (116.3 mmol) of4-bromophenylacetic acid, 24.1 g (174.4 mmol) of potassium carbonate and10.2 mL (127.9 mmol) of iodoethane in 250 mL of acetonitrile was heatedat 70° C. for 16 hours. The mixture was cooled to ambient temperature,diluted with 200 mL of ethyl acetate and washed once with 200 mL ofsaturated aqueous sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted three times with 75 mL each of ethylacetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo to afford 16.2 g (57%) of the title compound.

B. Phenyl 3-carbethoxy-3-(4-bromophenyl)propyl-sulfonate: A solution of16.2 g (66.6 mmol) of material from Step A, 4.6 g (33.3 mmol) ofpotassium carbonate and 4.4 g (16.7 mmol) of 18-crown-6 in 130 mL oftoluene was heated to 90° C. and 6.1 g (33.3 mmol) of phenylvinylsulfonate in 35 mL of toluene was added dropwise over one hour. Themixture was heated for 16 hours, cooled to ambient temperature anddiluted with 100 mL of ethyl acetate. The mixture was washed once with100 mL of half saturated brine. The organic layer was separated and theaqueous layer was extracted once with 50 mL of ethyl acetate. Thecombined organics were dried (MgSO₄), filtered and concentrated invacuc. Chromatography (Waters 2000, 15% ethyl acetate/hexane) of theresidue affords 4.8 g (17%) of the title compound.

Analysis calculated for C₁₈H₁₉O₅SBr: %C, 50.59; %H, 4.48. Found: %C,50.61; %H, 4.47.

Mass Spectrum: M+1=428.

C. Phenyl 3-carboxy-3-(4-bromophenyl)propylsulfonate: To a solution of4.8 g (11.3 mmol) of material from Step B in 40 mL of methanol was added6.8 mL of 2 N aqueous sodium hydroxide. The mixture was stirred atambient temperature for 5 hours and concentrated in vacuo. The residuewas dissolved in 50 mL of water and extracted three times with 20 mLeach of ethyl ether. The aqueous layer is acidified to pH 2 with 10%aqueous sodium bisulfate and extracted four times with 20 mL each ofethyl acetate. The combined ethyl acetate layers were dried (MgSO₄),filtered and concentrated in vacuo to afford 4.1 g (91%) of the titlecompound.

Analysis calculated for C₁₆H₁₅O₅SBr: %C, 48.13; %H, 3.79. Found: %C,48.17; %H, 3.53.

Mass Spectrum: M=399.

D. Phenyl 3-carboxamido-3-(4-bromophenyl)propyl-sulfonate: To a 0° C.solution of 4.1 g (10.2 mmol) of material from Step C and 2.0 mL (14.3mmol) of triethylamine in 23 mL of tetrahydrofuran was added 1.9 mL(14.3 mmol) of isobutyl chloroformate. The mixture was stirred at 0° C.for 25 minutes whereupon 11.2 mL (22.4 mmol) of a 2 N solution ofammonia in methanol was added. The cooling bath was removed and themixture stirred for 16 hours. The mixture was diluted with 50 mL ofethyl acetate and washed once with 50 mL of water. The organic layer wasseparated and the aqueous layer was extracted three times with 25 mLeach of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (250 g silica gel,35% acetone/hexane) of the residue affords 1.7 g (44%) of the titlecompound.

Mass Spectrum: M=398.

E. 4-(4-Bromophenyl)-1,1,3-trioxotetrahydro-1,2-thiazine: To a 0° C.solution of 9.0 mL (9.0 mmol) of a 1.0 M tetrahydrofuran solution ofpotassium tert-butoxide in 15 mL of tetrahydrofuran was added a solutionof 1.7 g (4.5 mmol) of material from Step D in 14 mL of tetra-hydrofurandropwise over 30 minutes. After stirring at 0° C. for two hours, thecooling bath was removed and stirring continued for 30 minutes. Themixture was diluted with 25 mL of water and extracted two times with 10mL each of ethyl ether. The aqueous portion was acidified to pH 2 with10% aqueous sodium bisulfate and extracted four times with 20 mL each ofethyl acetate. The combined ethyl acetate layers were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (75 g silica gel,0.25% acetic acid/40% acetone/hexane) of the residue affords 0.2 g (17%)of the title compound.

Analysis calculated for C₁₀H₁₀NO₃SBr: %C, 39.49; %H, 3.31; %N, 4.61.Found: %C, 39.74; %H, 3.23; %N, 4.42.

Mass Spectrum: M=304.

F. To a suspension of 0.13 g (0.4 mmol) of material from Step E and 0.2g (4.9 mmol) of sodium borohydride in 3 mL of dioxane was added 0.4 mL(4.9 mmol) of trifluoroacetic acid slowly via syringe. After stirring atambient temperature for 30 minutes the mixture was heated to reflux for5 hours. The mixture was cooled to ambient temperature, diluted with 3mL of methanol and stirred for 16 hours. The mixture was removed andstirring continued for 30 minutes. The mixture was concentrated invacuo, dissolved in 10 mL of ethyl acetate and washed two times with 5mL each of 1 N hydrochloric acid and once with 5 mL of 20% saturatedaqueous sodium bicarbonate/brine. The organics were dried (MgSO₄),filtered and concentrated in vacuo to afford 0.1 g (89%) of the titlecompound.

Analysis calculated for C₁₀H₁₂NO₃SBr: %C, 41.39; %H, 4.17; %N, 4.83.Found: %C, 41.10; %H, 4.34; %N, 4.76.

Mass Spectrum: M−1=289.

Preparation 50 D,L-penicillamine methyl ester hydrochloride

Through a suspension of 10.0 g (67.0 mmol) of D,L-penicillamine in 200mL of methanol was bubbled hydrogen chloride for 5 minutes. The mixturewas refluxed for 16 hours, cooled to ambient temperature andconcentrated in vacuo The residue was suspended in ethyl ether, filteredand dried to afford 12.6 g (94%) of the title compound.

Mass Spectrum: M=163.

Preparation 51 N-(t-butoxycarbonyl)-4-tributylstannylaniline

A. N-(t-Butoxycarbonyl)-4-bromoaniline: To a solution of 6.0 g (39.4mmol) of 4-bromoaniline in 30 mL of tetrahydrofuran was added 69.8 mL(69.8 mmol) of a 1.0 M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran. To the mixture was added 7.6 g (34.9 mmol) ofdi-t-butyldicarbonate in 10 mL of tetrahydrofuran. The mixture wasstirred at ambient temperature for one hour and concentrated in vacuo.The residue was dissolved in 50 mL of ethyl acetate and washed once with50 mL of 10% aqueous sodium bisulfate. The organic layer was separatedand the aqueous layer was extracted two times with 25 mL each of ethylacetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (250 g of silica gel, 10% ethylacetate/hexane) of the residue afforded 5.0 g (53%) of the titlecompound.

Analysis calculated for C₁₁H₁₄NO₂Br: %C, 48.55; %H, 5.19; %N, 5.15.Found: %C, 48.81; %H, 5.29; %N, 4.95.

Mass Spectrum: M−1=271.

B. A degassed solution of 4.9 g (18.0 mmol) of material from Step A, 2.6mL (18.9 mmol) of triethylamine, 9.6 mL (18.9 mmol) of bis(tributyltin)and 1.0 g (0.9 mmol) of tetrakis(triphenylphosphine)palladium(0) in 45mL of toluene was heated to 100° C. for 5 hours. The mixture was cooledto ambient temperature and diluted with 40 mL of ethyl acetate. Themixture was washed once with 50 mL of 10% aqueous sodium bisulfate, theorganics separated and the aqueous layer extracted three times with 20mL each of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (400 g of silica gel,5% ethyl acetate/hexane) of the residue afforded 1.4 g (16%) of thetitle compound.

Mass Spectrum: M+1=483.

Preparation 52 N-2-(4-tri-n-butylstannylphenyl)propyl methanesulfonamide

The title compound (3.6 g) was prepared by the method of Preparation 40starting from the product of Example 1.

Preparation 53 N-2-(4-(3-thienyl)phenyl)propyl amine

A. 2-(3-thienyl)phenyl-N-(t-butoxycarbonyl)propyl amine: To a solutionof 0.7 g (2.2 mmol) of material from Preparation 4, 0.3 g (2.4 mmol)thiophene-3-boronic acid and 0.46 g (3.3 mmol) of potassium carbonate in5 mL of dioxane and 1 mL of water was added 0.025 g (0.11 mmol) ofpalladium(II)acetate and 0.058 g (0.22 mmol) triphenylphosphine. Themixture was heated at 100° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of brine was added. The organic layer was separatedand dried (MgSO₄), filtered and concentrated in vacuc. Chromatography(25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded0.44 g (60%) of the title compound.

B. A solution of 0.4 g (1.3 mmol) of material from Preparation 53A in 4mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred atambient temperature for 3 h. The mixture was concentrated in vacuo andthe residue was dissolved in 5 mL ethyl acetate and 5 mL saturatedsodium bicarbonate. The organic layer was separated and the aqueouslayer extracted three times with 5 mL of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo toafford 0.21 g (74%) of the title compound.

Preparation 54A 4-(N,N-dibenzylamino)phenylacetonitrile

A solution of 4-aminophenylacetonitrile (20 g, 151.3 mmol) in dry DMF(150 ml) was treated with potassium carbonate (50.1 g, 363.1 mmol),benzyl bromide (54.4 g, 318 mmol), and potassium iodide (5 g, 0.2 30.3mmol). The reaction mixture was stirred at room temperature for 12 h.Water (100 ml) was added to the mixture and the organic was extractedwith ether (3×200 ml). The combined organic fraction was washed withbrine (200 ml), dried over sodium sulfate and concentrated. The crudeproduct was further purified by flash chromatography (SiO₂, 20% EtOAc:Hexanes) to give 36.2 g (76%) of the pure product. NMR was consistentwith the proposed title structure. Field Desorption

Mass Spectrum: M⁺=312.

Preparation 54B 1-chloroprop-2-yl sulfonyl chloride

To a 0° C. saturated solution of chlorine in 100 mL of water was addeddropwise 15.7 mL (200 mmol) of propylene sulfide while chlorine wasbubbled through the mixture. The mixture was stirred at 0° C. for onehour after addition. The resulting oil was separated and the aqueousportion was extracted two times with 20 mL each of dichloromethane. Thecombined organics were dried (CaCl₂), filtered and concentrated invacuo. Vacuum distillation afforded 10.8 g (30%) of the title compound.

Field Desorption Mass Spectrum: M−1=176.

Preparation 55 2-(4-(N,N-dibenzylamino)phenyl)propionitrile

A −78° C. solution of the material from Preparation 54A (22.8 g, 73mmol) in dry THF (70 ml) was treated with lithiumbis(trimethylsilyl)amide (1M in THF, 76.6 ml, 76.6 mmol). The resultingmixture was stirred at −78° C. for 1 h. Methyl iodide (4.8 ml, 76.6mmol) was added to the mixture. The reaction mixture was stirred at −78° C. for 1 h and gradually was allowed to warm to room temperature over12 h. Hydrochloric acid (0.2 M, 100 ml) was added to the mixture and theorganic was extracted with ether (3×200 ml). The combined organicfraction was washed with water (3×200 ml), brine (200 ml), dried oversodium sulfate and concentrated. The crude product was further purifiedby flash chromatography (SiO₂, 20% EtOAc: Hexane) to give 22.6 g (95%)of the pure product. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=326.

Preparation 56 2-(4-(N,N-dibenzylamino)phenyl)propylamine hydrochloride

A 0° C. solution of the material from Preparation 55 (23.6 g, 72.3 mmol)in dry THF (100 ml) was treated with borane methylsulfide (10 M in THF,8 ml, 80 mmol). The reaction mixture was stirred while refluxing for 3h. The solution was cooled down to room temperature and was treated witha saturated solution of hydrochloric acid in methanol until a whiteprecipitate formed. The solvent was removed in vacuo and the resultingwhite solid was triturated with ether (4×100 ml). The desiredhydrochloric salt was dried under vacuo to give 28.2 g (97%) of the pureproduct which was used in next step without any further purification.NMR was consistent with the proposed title structure.

Preparation 57 N-2-(4-(N′,N′-dibenzylamino)phenyl)propyl2-propanesulfonamide

A 0° C. suspension of the material from Preparation 56 (15.2 g, 37.7mmol) in dichloromethane (125 ml) was treated with triethylamine (11.4g, 113 mmol) followed by 2-propylsulfonyl chloride (9.2 g, 56.5 mmol).The reaction mixture was stirred at 0° C. for 1 h and at roomtemperature for 6 h. The reaction was stopped by the addition of water(100 ml). Organic was extracted with dichloromethane (3×200 ml). Thecombined organic fraction was washed with hydrochloric acid (0.2 M 100ml), water (3×200 ml), brine (100 ml), dried over sodium sulfate, andconcentrated in vacuo to give the crude material which was furtherpurified by flash chromatography (SiO₂, 30% EtOAc: Hexane) to give 10.32g (63%) of the title compound. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=436.

Preparation 58 N-2-(4-aminophenyl)propyl 2-proranesulfonamide

A solution of the product from Preparation 57 (2.5 g, 5.72 mmol) in EtOH(30 ml) was treated with ammonium formate (0.4 g, 6.3 mmol) andpalladium on carbon (0.25 g, 10 mole %). The reaction mixture wasstirred at room temperature for 6 h. The mixture was filtered through acelite cake and the filtrate was concentrated in vacuo to give 1.36 g ofthe pure product (93%). NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=257.

Preparation 59N-t-butyloxycarbonyl-N-2-(4-(N′,N′-dibenzylamino)phenyl)propyl2-propanesulfonamide

A solution of the material from Preparation 57 (2.5 g, 5.72 mmol) in drydichloromethane (25 ml) was treated with di-t-butyl dicarbonate (1.47 g,6.3 mmol) and 4-dimethylaminopyridine (0.37 g, 2.8 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction wasstopped by the addition of water (20 ml). Organic was extracted withether (3×30 ml). The combined organic fraction was washed with a 20%solution of sodium hydrogensulfate (2×30 ml), water (3×100 ml), brine(30 ml), dried over sodium sulfate, and concentrated in vacuo to givethe crude material which was further purified by flash chromatography(SiO₂, 30% EtOAc: Hexane) to give 3.07 g (100%) of the title compound.NMR was consistent with the proposed title structure. Field DesorptionMass Spectrum: M⁺=XXX.

Preparation 60 N-t-butyloxycarbonyl-N-2-(4-aminophenyl)propyl2-propanesulfonamide

A solution of the product from Preparation 59 (3.07 g, 5.72 mmol) inEtOH (30 ml) was treated with ammonium formate (0.54 g, 8.6 mmol) andpalladium on carbon (0.3 g, 10 mole %). The reaction mixture was stirredat room temperature for 6 h. The mixture was filtered through a celitecake and the filtrate was concentrated in vacuo to give 1.9 g (93%) ofthe title compound. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=257.

Preparation 61 2-(4-nitrophenyl)propionitrite

A −15° C. solution of 4-nitroacetophenone (16.5 g, 100 mmol) andtosylmethyl isocyanide (29.3 g, 150 mmol) in methoxyethyl ether (400 ml)was slowly treated with a room temperature solution of the potassiumt-butoxide (28 g, 250 mmol) in t-butanol (200 ml). The reaction mixturewas stirred at −15° C. for 1 h and then allowed to warm to roomtemperature over night. Water (100 ml) was added to the mixture andorganic was extracted with ether (3×200 ml). The combined organicfraction was washed with water (3×200 ml), brine (100 ml), dried oversodium sulfate, and concentrated in vacuo to give the crude materialwhich was further purified by flash chromatography (SiO₂, 30% EtOAc:Hexane) to give 13.6 g (77%) of the title compound. NMR was consistentwith the proposed title structure. Field Desorption Mass Spectrum:M⁺=225.

Preparation 62 2-(4-nitrophenyl)propylamine

A 0° C. solution of the material from Preparation 61 (11.8 g, 67 mmol)in dry THF (200 ml) was treated with borane tetrahydrofuran (1 M in THF,72 ml, 72 mmol). The reaction mixture was stirred at room temperaturefor 16 h. A solution of THF:MeOH (1:1, 10 ml) and sodium hydroxide (5 N,40 ml) were added to the reaction mixture stepwise and the mixture wasrefluxed for 5 h. The reaction mixture was allowed to cool to roomtemperature. Organic was extracted with dichloromethane (3×100 ml). Thecombined organic fraction was washed with water (3×200 ml), brine (100ml), dried over potassium carbonate, and concentrated in vacuo to givethe crude material which was further purified by flash chromatography(SiO₂, 5% MeOH: CH₂Cl₂) to give 8.5 g (71%) of the pure product. NMR wasconsistent with the proposed title structure. Field Desorption MassSpectrum: M⁺=181.

Preparation 63 N-2-(4-nitrophenyl)propyl 2-propanesulfonamide

A 0° C. suspension of the material from Preparation 62 (8.2 g, 45.3mmol) in dichloromethane (200 ml) was treated with1,8-diazabicyclo[5.4.0]undec-ene (7.6 g, 49.8 mmol) followed by2-propylsulfonyl chloride (12 g, 49.8 mmol). The reaction mixture wasstirred at 0° C. for 1 h and at room temperature for extra 12 h. Thereaction was stopped by the addition of water (100 ml). Organic wasextracted with dichloromethane (3×200 ml). The combined organic fractionwas washed with water (3×200 ml), brine (100 ml), dried over potassiumcarbonate, and concentrated in vacuo to give the crude material whichwas further purified by flash chromatography (SiO₂, 30% EtOAc: Hexane)to give 8.9 g (68%) of the pure product. NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺=287.

Preparation 64 N-2-(4-aminophenyl)propyl 2-propanesulfonamide

A degassed solution of the material from Preparation 63 (8.75 g, 31mmol) in ethyl acetate (200 ml) was treated with palladium on carbon (4g, 50 mol %). The mixture was shaken under 60 psi of hydrogen gas for 2h. The reaction mixture was filtered through a celite cake and thefiltrate was concentrated in vacuo to yield 7.44 g (94%) of the pureproduct. NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺=257.

Preparation 65 N-2-(4-(benzylamino)phenyl)propyl 2-propanesulfonamide

In a pressure tube a degassed solution of bromide from Preparation 39 (3g, 9.7 mmol) in anhydrous toluene (40 ml) was treated with benzylamine(1.27 ml, 11.6 mmol),tris(dibenzylideneacetone)dipalladium(0) (170 mg,0.19 mmol), S(−)-BINAP (360 mg, 0.58 mmol), and sodium t-butoxide (1.95mg, 20.3 mmol). The reaction mixture was stirred at 80° C. for 16 h. Themixture was cooled to room temperature. Water (5 ml). was added to themixture and organic was extracted with ether (3×% ml). The combinedorganic fraction was washed with water (2×5 ml), brine (5 ml), driedover sodium sulfate, and concentrated in vacuo to give the crude productwhich was further purified by flash chromatography (SiO2, 20% EtOAc:hexanes) to give 1.9 g (58%) of a yellow oil as the title compound. NMRwas consistent with the proposed title structure.

Preparation 66 2-(4-aminophenyl)propyl 2-propanesulfonamide

A solution of the product from Preparation 65 (1.5 g, 4.33 mmol) inEtOAc (30 ml) was treated with ammonium formate (0.41 g, 6.5 mmol) andpalladium on carbon (0.15 g, 10 mole %). The reaction mixture wasstirred at room temperature for 3 h. The mixture was filtered through acelite cake and the filtrate was concentrated in vacuo to give 1.1 g ofthe title compound (98%). NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=257.

Preparation 67 N-2-(4-(carboxy)phenyl)propyl 2-propanesulfonamide

A −85° C. solution of the product from Preparation 39 (220 mg, 0.65mmol) in dry THF (2 ml) was treated with n-butyl lithium solution (0.87ml, 1.37 mmol, 1.6 M solution). The reaction mixture was stirred for 10minutes at −85° C. and then carbon dioxide gas was bubbled into themixture for 1 minutes. The reaction mixture was allowed to warm to roomtemperature. Water (5 ml) and concentrated hydrochloric acid (3 ml) wereadded to the mixture and organic was extracted with ether (3×10 ml). Thecombined organic fractions was washed with water (2×10 ml), brine (5ml), dried over sodium sulfate, and concentrated in vacuo to yield 210mg (98%) of the pure product which was used in the next step withoutfurther purification.

Preparation 68 N-t-butyloxycarbonyl-4-piperazinoacetophenone

A solution of the 4-piperazinoacetophenone (10 g, 49 mmol) intetrahydrofuran:water (200 ml, 1:1 mixture) was treated with potassiumcarbonate (8.43 g, 58 mmol) and di-t-butyl dicarbonate (13.1 g, 53.9mmol). The reaction mixture was stirred at room temperature for 3 h.Water (300 ml) was added to the mixture and organic was extracted withethyl acetate (3×100 ml). The combined organic fraction was washed withwater (2×200 ml), brine (100 ml), dried over sodium sulfate, andconcentrated in vacuo to 17.41 g of the yellowish solid. The crudeproduct was further purified by Prep LC 2000 eluting with 30% EtOAc:Haxanes to give 10.9 g (73%) of the title compound as a white solid.Field Desorption Mass Spectrum: M⁺=305.

Preparation 69 2-(N-t-butyloxycarbonyl-4-piperazinophenyl)propionitrile

The title compound 1.8 g (16%) was prepared as a solid following themethod of Preparation 61, starting from the product of Preparation 68and using tosylmethyl isocyanide. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=316.

Preparation 70 2-(N-t-butyloxycarbonyl-4-piperazinophenyl)propylamine

The title compound 1.78 g (100%) was prepared as a solid following themethod of Preparation 62, starting from the product of Preparation 69and using borane methylsulfide. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=319.

Preparation 71 N-2-(N-t-butyloxycarbonyl-4-piperazinophenyl)propyl2-propanesulfonamide

The title compound 676 mg (61%) was prepared as a solid following themethod of Preparation 63, starting from the product of Preparation 70and using borane methylsulfide. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=319.

Preparation 72 N-2-(4-piperazinophenyl)propyl 2-propanesulfonamide

A solution of the material from Preparation of 71 (800 mg, 1.88 mmol) indichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml).The reaction mixture was stirred at room temperature for 3 h. A 1Nsolution of the sodium hydroxide (10 ml) was added to the mixture andthe organic was extracted with dichloro-methane (3×20 ml). The combinedorganic fraction was washed with water (2×20 ml), brine (20 ml), driedover potassium carbonate, and concentrated in vacuo to give 560 mg (91%)of the pure product. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=319.

Preparation 73 N-2-(N-benzoyl-4-piperazinophenyl)propyl2-propanesulfonamide

A 0° C. solution of material from Preparation 72 (80 mg, 0.25 mmol) indichloromethane (10 ml) was treated with triethylamine (28 mg, 0.27mmol) and benzoic anhydride (61 mg, 0.27 mmol). The reaction mixture wasstirred at 0° C. for 30 minutes. Water (5 ml) was added to the mixtureand the organic was extracted with dichloromethane (3×5 ml). Thecombined organic fraction was washed with water (2×5 ml), brine (5 ml),dried over potassium carbonate, and concentrated in vacuo to give 94 mg(87%) of the title compound. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=430.2.

Preparation 74 3-Tributyltin-2-cyclopenten-1-one

A −20° C. solution of hexabutylditin (4.6 g, 7.9 mmol) in dry THF (15ml) was treated with nBuLi (4.9 ml, 7.9 mmol, 1.6 M solution inhexanes). The reaction mixture was stirred at −20° C. for 30 min andthen cooled to −78° C. The mixture was treated with3-ethoxy-2-cyclopenten-1-one (1.0 g, 7.9 mmol) and the reaction mixturestirred at −78° C. for 30 min. A saturated, aqueous solution of ammoniumchloride (2 ml) followed by water (30 ml) and the organic extracted withhexanes (2×30 ml). The combined organic layers were washed with brine(20 ml), dried over magnesium sulfate and concentrated in vacuo. Thisgave 2.7 g (93%) of the crude product which was used without furtherpurification. NMR was consistent with the title structure.

Preparation 75 N-2-(4-(1-(3-oxo)cyclopentenyl)phenyl)prolyl2-propanesulfonamide

A solution of the product of Preparation 39 (1.0 g, 3.22 mmol) in dry,degassed THF (15 ml) was treated with the product of Preparation 74 (1.8g, 4.83 mmol), and dichlorobis(triphenylphosphine)palladium(II) (45 mg,0.06 mmol). The reaction mixture was heated to reflux for 48 h. Themixture was cooled and partitioned between acetonitrile and hexanes. Theacetonitrile layer was washed with hexanes (3×20 ml), then concentratedin vacuo. The crude product was further purified by flash chromatography(SiO₂, 70% EtOAc: hexanes) to give 0.71 g (68%) of title compound as apure product. NMR was consistent with proposed title structure. FieldDesorption Mass Spectrum: M⁺=321.1.

Preparation 76 1-(4-bromophenyl)-2,5-dimethylpyrrole

4-Bromoaniline (56.0 g., 0.33 Mol.), 2,5-hexanedione (37.6 g., 0.33Mol), and acetic acid (5 ml) were placed into Toluene (500 ml) andheated under reflux for 8 hours employing a dean stark trap to removethe water from the reaction. The reaction was cooled to room temperatureand concentrated under reduced vacuum. The resulting oil was taken intoethyl acetate, washed one time each with 2N hydrochloric acid, 2N NaOH,and H₂O, dried over Na₂SO₄, and concentrated under reduced vacuum toyield a brown solid. Material was purified by silica gel flashchromatography eluting with hexane. Concentration of the appropriatefractions yielded 55.0 gm. of a light yellow solid. (68%) NMR wasconsistent with the proposed title structure. Field Desorption MassSpectrum: M⁺ 249 m.p. 71°-73° C.

Preparation 77 1-(4-acetylphenyl)-2,5-dimethylpyrrole

A −30° C. solution of the material from Preparation 76 (25.0 g, 0.1 mol)in dry ether (500 ml) was treated with n-butyllithium (70 ml of 1.6 M,0.12 mol) and stirred for one hour at −30° C. N,N Dimethyl acetamide(9.7 g, 0.12 mol) was added and the reaction continued at thistemperature for 4 hours. The reaction was then allowed to warm to roomtemperature and stirred over night at this temperature. In the morning,the mixture was diluted with ethyl acetate and the combined organiclayers were washed one time each with 2.0 N hydrochloric acid and H₂O,dried over Na₂SO₄, and concentrated under reduced vacuum to yield awhite solid. The material was triturated in hexane and filtered to yield12.8 gm. of a white solid. m.p. 106°-108° C. (60%) NMR was consistentwith the proposed title structure. Field Desorption Mass Spectrum: M⁺214

Preparation 78 1-(4-(1-cyano)ethylphenyl)-2,5-dimethylpyrrole

The starting ketone from Preparation 77 (44.3 g, 0.21 mol), tosylmethylisocyanide (40.6 g, 0.21 mol), potassium-t-butoxide (39.2 g, 0.35 mol),and t-butyl alcohol (250 ml) were reacted in ethylene glycol dimethylether (500 ml) as described in Preparation 61 to yield a yellow solid.Purification was achieved by silica gel flash chromatography elutingwith hexane/ethyl acetate 4:1 to yield 32.3 gm. of yellow crystals. m.p.79°-80° C. (68%) Field desorption Mass Spectrum: M⁺ 225

Preparation 79 1-(4-(2-(2-cyano)propyl)phenyl)-2,5-dimethylpyrrole

A −78° C. solution of material from Preparation 78 (7.0 g, 32 mmol) indry tetrahydrofuran (100 ml) was treated with lithium(bis)trimethylsilylamide (40 ml of 1.0M, 1.3 eq.). After stirring 30minutes at this temperature, methyl iodide (2.6 ml, 1.3 eq.) was addeddropwise and the reaction was allowed to warm to room temperature. Themixture was diluted with ether and the combined organic layers werewashed once with H₂O, dried over K₂CO₃, and concentrated under reducedvacuum to yield 7.61 gm. of a yellow solid. Material was purified viasilica gel chromatography eluting with a solvent of hexane/ethyl acetate9:1 to yield 6.30 gm. of a yellow solid. m.p. 135°-137° C. (83%). Fielddesorption Mass Spectrum: M⁺+1 239

Preparation 801-(4-(2-(3-amino-2-methyl)propyl)phenyl-2,5-dimethylpyrrole

The nitrile from Preparation 79 (6.23 g, 26.2 mmol) in tetrahydrofuran(250 ml) was treated with borane-THF complex (17.1 ml, 1.0 M) asdescribed in Preparation 62 to yield 6.37 gm. of a foam. This materialwas purified via silica gel chromatography eluting with a gradientsolvent of dichloromethane to dichloromethane/methanol 9:1 to yield 4.08gm. of a white solid. m.p. 95°-97° C. (65%). NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺ 243

Preparation 81 N-2-(4-(2,5-dimethylpyrrole)phenyl)-2-methylpropyl2-propanesulfonamide

The amine from Preparation 80 (4.0 g, 16.6 mmol) was treated with1,8-diazabicyclo[5.4.0]undec-ene (3.28 g, 1.3 eq) and 2-propylsulfonylchloride (3.2 ml, 1.3 eq) in dichloromethane (80 ml) as described inPreparation 63 to yield 6.1 gm. of a yellow oil. This material waspurified via silica gel chromatography eluting with an isocratic solventof hexane/ethyl acetate 4:1 to yield 4.3 gm. of a white solid. m.p.110°-112° C. (62%). NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺ 349

Preparation 82 N-2-(4-aminophenyl)-2-methylpropyl 2-propanesulfonamide

The sulfonamide from Preparation 81 (2.17 g, 6.3 mmol) was treated withhydroxylamine hydrochloride (2.0 g, 13.8 mmol) and potassium hydroxide(0.96 g, 20.0 mmol) in absolute ethanol (16 ml) and water (6 ml). Thismixture was refluxed for 24 hours. The solution was cooled to roomtemperature and poured into H₂O and the desired product was extractedwith ether. The organic layer was backwashed once with H₂O, dried overK₂CO₃ and concentrated under reduced pressure to yield 1.57 gm. as anoil. This material was purified via silica gel chromatography elutingwith an isocratic solvent of hexane/ethyl acetate 1:1 to yield 1.41 gm.of a white solid. m.p. 87°-88° C. (84%). NMR was consistent with theproposed title structure. Field Desorption Mass Spectra: M⁺ 271

Preparation 83 N-2-(4-nitrophenyl)propyl N,N-dimethylsulfamide

The nitro-amine from Preparation 62 (1.8 g, 0.01 Mol) was treated with1,8-diazobicyclo[5.4.0]undec-ene (1.70 g, 1.1 eq) andN,N-dimethylsulfamoyl chloride (2.1 ml, 1.1 eq) in dichloromethane (40ml) as stated in Preparation 63 to yield 3.60 gm. of a dark oil. Thismaterial was purified via silica gel chromatography eluting with agradient solvent of hexane/ethyl acetate 9:1 to hexane/ethyl acetate 7:3to yield 1.0 gm. of a white solid. m.p. 79°-81° (50%). Field desorptionMass Spectrum: M⁺ 288

Preparation 84 N-2-(4-aminophenyl)propyl N,N-dimethylsulfamide

The nitro-sulfamide from Preparation 83 (1.0 g, 3.5 mmol) was treatedwith 5% Pd/C (2.0 g, excess) and hydrogen in ethyl acetate (100 ml) asdescribed in Preparation 64 to yield 820 mg. of a white solid. m.p.101.5°-103° C. (91%). Field desorption Mass Spectrum: M⁺ 258

Preparation 85 4-Bromophenylacetyl chloride

A solution of 50.0 g (232 mmol) of 4-bromophenylacetic acid in 150 mL ofthionyl chloride was stirred at room temperature for 18 h. The mixturewas concentrated in vacuo to afford 54 g (100%) of the title compound.

Preparation 86 (R)-(−)-4-Benzyl-3-(4-bromophenylacetyl)-2-oxazolidinone

A solution of 20.0 g (117 mmol) of (R)-(+)-4-benzyl-2-oxazolidinone in300 mL of tetrahydrofuran was cooled to −78° C. and 73.0 mL (117 mmol)of 1.6M n-Butyllithium was added dropwise. The mixture was stirred 30min then was slowly added via cannula to a solution of 25 g (107 mmol)of material from Preparation 85 in 150 mL of tetrahydrofuran at −78° C.The mixture was stirred for 1 hr and then 300 mL of 10% aqueous sodiumbisulfate was added. The organic layer was separated and the aqueouslayer was extracted three times with 100 mL each of ether. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (750 g of silica gel, 25% ethyl acetate/hexane) of theresidue afforded 27.4 g (68%) of the title compound.

Analysis calculated for C₁₈H₁₆BrNO₃: %C, 57.77; %H, 4.31; %N, 3.74.Found: %C, 57.62; %H, 4.21; %N, 3.74.

Field Desorption Mass Spectrum: M=374.

[α]_(D) ²⁰=−59.83 (c=1.04, CHCl₃).

Preparation 87(−)-4R-Benzyl-3-(2R-(4-bromophenyl)propionyl)-2-oxazolidinone

A solution of 48 g (128 mmol) of material from Preparation 86 in 200 mLof tetrahydrofuran was cooled to −78 ° C. and 141 mL (141 mmol) of 1Msodium bis(trimethyl-silyl)amide was added dropwise. The mixture wasstirred 60 min then a solution of 20 g (141 mmol) of iodomethane in 20mL of tetrahydrofuran was slowly added. The mixture was stirred for 60min at −78° C. and then allowed to warm to room temperature for 60 min.To the reaction was added 10% aqueous sodium bisulfate and the organiclayer was separated and the aqueous layer was extracted three times with100 mL each of ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (500 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 28.7 g (58%) of thetitle compound.

Analysis calculated for C₁₉H₁₈BrNO₃: %C, 58.78; %H, 4.67; %N, 3.61.Found: %C, 58.81; %H, 4.63; %N, 3.54.

Field Desorption Mass Spectrum: M=388.

[α]_(D) ²⁰=−110.4 (c=0.96, CHCl₃).

Preparation 88 (R)-(+)-2-(4-bromophenyl)propanol

A solution of 28.7 g (74 mmol) of material from Preparation 87 in 250 mLof ether was cooled to 0° C. and 74 mL (148 mmol) of 2Mlithiumborohydride in tetrahydrofuran was added dropwise. The mixturewas stirred for 2 hr then 1N sodium hydroxide was added and the mixturewas stirred until both organic and aqueous layers became clear. Theorganic layer was separated and the aqueous layer was extracted threetimes with 10 mL each of ethyl acetate. The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(800 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded12.3 g (79%) of the title compound.

Analysis calculated for C₉H₁₁BrO: %C, 50.26; %H, 5.15. Found: %C, 48.96;%H, 4.91.

Field Desorption Mass Spectrum: M+1=216.

[α]_(D) ²⁰=+13.79 (c=1.06, CHCl₃).

Preparation 89 (R)-2-(4-bromophenyl)propyl methanesulfonate

A solution of 12.2 g (56.7 mmol) of material from Preparation 88 and 8.7mL (62.4 mmol) of triethylamine in 180 mL of dichloromethane was cooledto 0° C. A solution of 4.8 mL (62.4 mmol) of methanesulfonyl chloride in10 mL of dichloromethane was added dropwise. The ice-bath was removedand the mixture was stirred at room temperature for 2 h. The mixture waswashed with 200 mL of 10% aqueous sodium bisulfate, the organic layerwas separated and the aqueous layer extracted three times with 60 mL ofether. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo afford 15.9 g (96%) of the title compound.

Preparation 90 (R)-2-(4-bromophenyl)propyl azide

A solution of 15.8 g (54 mmol) of material from Preparation 89 in 180 mLof N,N-dimethylformamide and 7.0 g (108 mmol) sodium azide was heated at80° C. for 5 h. The mixture was cooled and concentrated in vacuo. Theresidue was partitioned between 100 mL of water and 100 mL of ether. Theorganic layer was separated and the aqueous layer was washed three timeswith 30 mL each of ether. The combined organic extracts were dried(MgSO4), filtered and concentrated in vacuo to afforded 12.13 g (94%) ofthe title compound.

Preparation 91 (R)-(+)-2-(4-bromophenyl)propyl amine hydrochloride

A solution of 12.2 g (50.4 mmol) of material from Preparation 90 and14.5 g (55.4 mmol) of triphenylphosphine in 168 mL of tetrahydrofuranand 3.6 mL of water was stirred at room temperature for 18 h. Themixture was diluted with 100 mL of ether and 50 mL of brine. The organiclayer was removed and dried (MgSO4), filtered and concentrated in vacuo.The residue was dissolved in 100 mL of ether and to this was added 200mL of hydrochloric acid saturated ether. Filtration of the resultingsolid afforded 11.9 g (94%) of the title compound.

Analysis calculated for C₉H₁₃BrClN; %C, 43.14; %H, 5.23; %N, 5.59.Found: %C, 43.44; %H, 5.23; %N, 5.56.

Mass Spectrum: [M-HCl]=214.

[α]_(D) ²⁰=+24.06 (c=1.00, H₂O).

Preparation 92 (R)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine

To a solution of 5.0 g (20.0 mmol) of material from Preparation 91 in 30mL of chloroform and 30 mL of saturated sodium bicarbonate was added 4.3g (20.0 mmol) of di-tert-butyl dicarbonate. The solution was stirred atroom temperature for 18 h. The organic layer was separated and theaqueous layer was extracted three times with 10 mL each of chloroform.The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford 6.2 g (100%) of the title compound.

Preparation 93 (S)-(+)-4-Benzyl-3-(4-bromophenylacetyl)-2-oxazolidinone

Following the procedure of Preparation 86 and using(S)-(−)-4-benzyl-2-oxazolidinone instead of(R)-(+)-4-benzyl-2-oxazolidinone afforded 25.3 g (63%) of the titlecompound.

Analysis calculated for C₁₈H₁₆BrNO₃: %C, 57.77; %H, 4.31; %N, 3.74.Found: %C, 57.69; %H, 4.18; %N, 3.82.

Field Desorption Mass Spectrum: M=374.

[α]_(D) ²⁰=+59.35 (c=1.04, CHCl₃).

Preparation 94(+)-4-S-Benzyl-3-(2S-(4-bromophenyl)propionyl)-2-oxazolidinone

Following the procedure of Preparation 87 and using material fromPreparation 93 instead of material from Preparation 86 afforded 28.9 g(51%) of the title compound.

Analysis calculated for C₁₉H₁₈BrNO₃: %C, 58.78; %H, 4.67; %N, 3.61.Found: %C, 59.40; %H, 4.61; %N, 3.64.

Field Desorption Mass Spectrum: M=388.

[α]_(D) ²⁰=+114.8 (c=1.01, CHCl₃).

Preparation 95 (S)-(−)-2-(4-bromophenyl)propanol

Following the procedure of Preparation 88 and using material fromPreparation 94 instead of material from Preparation 87 afforded 12.3 g(79%) of the title compound.

Analysis calculated for C₉H₁₁BrO: %C, 50.26; %H, 5.15. Found: %C, 50.38;%H, 5.08.

Field Desorption Mass Spectrum: M+1=216.

[α]_(D) ²⁰=−13.25 (c=1.06, CHCl₃).

Preparation 96 (S)-2-(4-bromophenyl)propyl methanesulfonate

Following the procedure of Preparation 89 and using material fromPreparation 95 instead of material from Preparation 88 afforded 16.9 g(100%) of the title compound.

Preparation 97 (S)-2-(4-bromophenyl)propyl azide

Following the procedure of Preparation 90 and using material fromPreparation 96 instead of material from Preparation 89 afforded 13.0 g(94%) of the title compound.

Preparation 98 (S)-(−)-2-(4-bromophenyl)propyl amine hydrochloride

Following the procedure of Preparation 91 and using material fromPreparation 97 instead of material from Preparation 90 afforded 11.6 g(86%) of the title compound.

Analysis calculated for C₉H₁₃BrClN: %C, 43.14; %H, 5.23; %N, 5.59.Found: %C, 43.36; %H, 5.39; %N, 5.64.

Mass Spectrum: [M-HCl]=214.

[α]_(D) ²⁰=−25.3 (c=1.02, H₂O).

Preparation 99 (S)-2-(4-bromophenyl)-N-(t-butoxycarbonyl)propyl amine

Following the procedure of Preparation 92 and using material fromPreparation 98 instead of material from Preparation 91 afforded 5.9 g(94%) of the title compound.

Preparation 100 (R)-2-(4-(3-thienyl)phenyl)-N-(t-butoxycarbonyl)propylamine

To a solution of 2.0 g (6.4 mmol) of material from Preparation 92, 0.9 g(7.0 mmol) of thiophene-3-boronic acid and 1.3 g (9.6 mmol) of potassiumcarbonate in 20 mL of dioxane and 5 mL of water was added 0.4 g (0.32mmol) of tetrakis (triphenylphosphine)palladium(0). The mixture washeated at 100° C. for 18 h. The mixture was cooled to room temperatureand 20 mL of water and 20 mL of ether was added. The organic layer wasseparated and the aqueous layer was extracted three times with 10 mLeach of ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (150 g of silica gel,15% ethyl acetate/hexane) of the residue afforded 1.4 g (70%) of thetitle compound.

Preparation 101 (S)-2-(4-(3-thienyl)phenyl)-N-(t-butoxycarbonyl)propylamine

Following the procedure of Preparation 100 and using material fromPreparation 99 instead of material form Preparation 92 afforded 5.9 g(94%) of the title compound.

Preparation 102 2R-(4-(3-thienyl)phenyl)propyl amine

A solution of 1.4 g of material from Preparation 100 in 15 mL 25%trifluoroacetic acid/dichloromethane was stirred at room temperature for3 h. The mixture was concentrated in vacuo and the residue was dissolvedin 20 mL of 1N sodium hydroxide and 20 mL of ethyl acetate. The organiclayer was separated and the aqueous layer was extracted four times with10 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo to afford 0.85 g (89%) ofthe title compound.

Preparation 103 2S-(4-(3-thienyl)phenyl)propyl amine

Following the procedure of Preparation 102 and using material fromPreparation 101 instead of material from Preparation 100 afforded 0.9 g(94%) of the title compound.

EXAMPLE 1 N-2-(4-Bromophenyl)propyl methanesulfonamide

To a solution of 2.8 g (11.3 mmol) of material from Preparation 2 atambient temperature in 30 mL of dichloro-methane and 30 mL of 10%aqueous sodium hydroxide was added 1.1 mL (13.6 mmol) of methanesulfonylchloride. After 1 hour an additional 1.1 mL (13.6 mmol) ofmethanesulfonyl chloride was added and stirring continued for 1.5 hours.The organic portion was separated and the aqueous portion was extractedtwice with 25 mL each of dichloromethane. The combined organics werewashed once with 25 mL of 10% aqueous sodium bisulfate, dried (Na₂SO₄),filtered and concentrated in vacuo to afford 2.7 g (81%) of the titlecompound.

Analysis calculated for C₁₀H₁₄NBrO₂S: %C, 41.11; %H, 4.83; %N, 4.79.Found: %C, 40.92; %H, 4.78; %N, 4.85.

Field Desorption Mass Spectrum: M−1=291

EXAMPLE 2 N-2-(4-(3-fluorophenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1,1.1 g (7.7 mmol) of 3-fluorobenzeneboronic acid and 1.1 g (7.7 mmol) ofpotassium carbonate in 30 mL of toluene was added 0.2 g (0.3 mmol) ofbis(triphenylphosphine)palladium(II) dichloride. The mixture was heatedto 100° C. for 16 hours, cooled to ambient temperature and diluted with20 mL of ethyl acetate. The mixture was washed once with 25 mL water andthe organic portion was separated. The aqueous portion was extractedthree times with ethyl acetate and the combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography on 75 gsilica gel (20% ethyl acetate/toluene) followed by recrystallizationfrom ethyl ether, filtration and drying in vacuo at 60° C. afforded 0.15g (9%) of the title compound.

Analysis calculated for C₁₆H₁₈NFO₂S.0.25H₂O: %C, 61.62; %H, 5.98; %N,4.49. Found: %C, 61.67; %H, 5.83; %N, 4.64.

Field Desorption Mass Spectrum: M=307

EXAMPLE 3 N-2-(4-(3-formylphenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1,1.2 g (8.1 mmol) of 3-formylbenzeneboronic acid and 1.1 g (8.1 mmol) ofpotassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) oftetrakis-(triphenyl-phosphine)palladium(0). The mixture was heated to100° C. for 16 hours whereupon 5 mL of water was added and heatingcontinued for 1 hour. The mixture was then cooled to ambient temperatureand 10 mL of water was added. The organic portion was separated and theaqueous portion was extracted twice with ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography on 50 g silica gel (40% ethyl acetate/hexane) afforded0.7 g (41%) of the title compound.

Analysis calculated for C₁₇H₁₉NO₃S: %C, 64.33; %H, 6.03; %N, 4.41.Found: %C, 64.33; %H, 6.06; %N,4.01.

Field Desorption Mass Spectrum: M=317

EXAMPLE 4 N-2-(4-(4-formylphenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1,1.2 g (8.1 mmol) of 4-formylbenzeneboronic acid and 1.1 g (8.1 mmol) ofpotassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) oftetrakis(triphenyl-phosphine)palladium(0). The mixture was heated to100° C. for 4 hours whereupon 0.3 g (2.0 mmol) of 4-formylbenzeneboronicacid and 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)-palladium(0)was added and heating continued for 16 hours. To this solution was added5 mL of water and heating continued for 1 hour. The mixture was thencooled to ambient temperature and 10 mL of water was added. The organicportion was separated and the aqueous portion was extracted twice withethyl acetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography on 50 g silica gel (50% ethylacetate/hexane) afforded a solid which was recrystallized frombromobutane/ethyl acetate, filtered and dried in vacuo at 60° C. toafford 0.5 g (32%) of the title compound.

Analysis calculated for C₁₇H₁₉NO₃S: %C, 64.33; %H, 6.03; %N, 4.41.Found: %C, 64.62; %H, 5.97; %N, 4.36.

Field Desorption Mass Spectrum: M=317

EXAMPLE 5 N-2-(4-(3-thienyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1,1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 mmol) ofpotassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) oftetrakis(triphenyl-phosphine)palladium(0). The mixture was heated to100° C. for 4 hours, cooled to ambient temperature and diluted with 20mL of ethyl acetate. The mixture was then washed once with water, andthe organic portion was separated. The aqueous portion was extractedtwice with ethyl acetate and the combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography on 50 g silica gel(35% ethyl acetate/hexane) afforded a solid which was recrystallizedfrom bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g(27%) of the title compound.

Analysis calculated for C₁₄H₁₇NO₂S₂: %C, 56.92; %H, 5.80; %N, 4.74.Found: %C, 57.00; %H, 5.92; %N,4.78.

Field Desorption Mass Spectrum: M=295

EXAMPLE 6 N-2-(4-(2-methoxyphenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.0 g (3.4 mmol) of material from Example 1,0.8 g (5.1 mmol) of 2-methoxybenzeneboronic acid and 0.7 g (5.1 mmol) ofpotassium carbonate in 15 mL of dioxane and 5 mL of water was added 0.2g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated to 100° C. for 16 hours. The reaction mixture was cooled toambient temperature, diluted with 10 mL of water and extracted threetimes with ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography on 50 g silica gel(35% ethyl acetate/hexane) afforded 1.0 g (90%) Of the title compound asa viscous oil.

Analysis calculated for C₁₇H₂₁NO₃S: %C, 63.92; %H, 6.62; %N, 4.39.Found: %C,63.68; %H, 6.78; %N, 4.23.

Field Desorption Mass Spectrum: M=319

EXAMPLE 7 N-2-(4-(2-fluorophenyl)phenyl)ethyl)2-proranesulfonamide

A. (2-(4-bromophenyl)-N-(t-butoxycarbonyl)ethylamine: To a solution of10.0 g (50.0 mmol) of 4-bromophenethylamine in 100 mL of chloroform and100 mL of saturated sodium bicarbonate was added 11.0 g (50.0 mmol) ofdi-tert-butyl dicarbonate. The solution was stirred at ambienttemperature for 1 hour. The organic layer was separated and the aqueouslayer was extracted three times with 30 mL each of chloroform. Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo to afford 15 g (100%) of the title compound.

B. 2-(4-(2-fluorophenyl)phenyl)-N-(t-butoxycarbonyl)-phenyl ethylamine:To a degassed solution of 7.9 g (26.2 mmol) of material from Step A, 5.5g (39.3 mmol) of material from Preparation 3 and 5.4 g (39.3 mmol) ofpotassium carbonate in 90 mL of toluene was added 1.5 g (1.3 mmol) oftetrakis-(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 3 hours. The mixture was cooled to ambient temperature and 90 mLof water was added. The organic layer was separated and the aqueouslayer was extracted three times with 30 mL each of ethyl acetate. Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. Chromatography (400 g of silica gel, 15% ethyl acetate/hexane)of the residue afforded 7.1 g of material that was triturated in hexaneto afford 3.5 g (42%) of the title compound.

C. 2-(4′-(2-fluorobiphenyl))ethylamine: A solution of 3.5 g of materialfrom Step B in 40 mL 20% trifluoroacetic acid/dichloromethane wasstirred at ambient temperature for 1 hour. The mixture was concentratedin vacuo to afford 3.9 g (100%) of the title compound.

D. A solution of 1.0 g (3.0 mmol) of material from Step C and 1 mL (7.6mmol) of triethylamine in 10 mL of dichloro-methane was cooled to 0° C.A solution of 0.33 mL (3.0 mmol) of isopropylsulfonyl chloride in 5 mLof dichloromethane was added dropwise. The ice-bath was removed and themixture was stirred at ambient temperature for 1 hour. The mixture wasdiluted with 10 mL of ether and washed with 20 mL of 10% aqueous sodiumbisulfate, the organic layer was separated and the aqueous layerextracted three times with 10 mL each of ether. The combined organicswere dried (MgSO₄), filtered and concentrated in vacuo to afford 0.5 g(52%) of the title compound.

Analysis calculated for C₁₇H₂₀FNO₂S .0.25 H₂O: %C, 62.65; %H, 6.34; %N,4.30. Found: %C, 62.62; %H, 6.15; %N, 4.49.

Field Desorption Mass Spectrum: M=321.

EXAMPLE 8 N-2-(4-(2-fluorophenyl)phenyl)propyl ethenesulfonamide

A solution of 1.0 g (4.4 mmol) of material from Preparation 6 and 0.67mL (4.8 mmol) of triethylamine in 15 mL of dichloromethane was cooled to0° C. A solution of 0.46 mL (4.4 mmol) of 2-chloro-1-ethanesulfonylchloride in 2 mL of dichloromethane was added dropwise. The ice-bath wasremoved and the mixture was stirred at ambient temperature for 1 hour.The mixture was diluted with 15 mL of ether and washed with 15 mL of 10%aqueous sodium bisulfate, the organic layer was separated and theaqueous layer extracted three times with 5 mL each of ether. Thecombined organics were dried (MgSO₄), filtered and concentrated invacuo. Chromatography (25 g of silica gel, 30% ethyl acetate/-hexane) ofthe residue afforded 0.6 g (43%) of the title compound.

Analysis calculated for C₁₇H₁₈FNO₂S: %C, 63.93; %H, 5.68; %N, 4.39.Found: %C, 63.98; %H, 5.58; %N, 4.42.

Field Desorption Mass Spectrum: M=319.

EXAMPLE 9 N-2-(4-(2-fluorophenyl)phenyl)propyl ethanesulfonamide

A solution of 0.2 g (0.80 mmol) of material from Preparation 6 and 0.13mL (0.95 mmol) of triethylamine in 5 mL of dichloromethane was cooled to0° C. A solution of 0.076 mL (0.80 mmol) of ethanesulfonyl chloride in 1mL of dichloromethane was added dropwise. The ice-bath was removed andthe mixture was stirred at ambient temperature for 16 hours. The mixturewas washed with 5 mL of 10% aqueous sodium bisulfate, the organic layerwas separated and the aqueous layer extracted one time with 5 mL ofdichloro-methane. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (25 g of silica gel, 35% ethylacetate/hexane) of the residue afforded 0.20 g (78%) of the titlecompound.

Analysis calculated for C₁₇H₂₀FNO₂S: %C, 63.53; %H, 6.27; %N, 4.36.Found: %C, 63.24; %H, 6.27; %N, 4.39.

Field Desorption Mass Spectrum: M=321.

EXAMPLE 10 N-2-(4-(2-fluorophenyl)phenyl)propyl 2-propanesulfonamide

A solution of 0.2 g (0.80 mmol) of material from Preparation 6 and 0.13mL (0.95 mmol) of triethylamine in 5 mL of dichloromethane was cooled to0° C. A solution of 0.090 mL (0.80 mmol) of isopropylsulfonyl chloridein 1 mL of dichloromethane was added dropwise. The ice-bath was removedand the mixture was stirred at ambient temperature for 16 hours. Themixture was washed with 5 mL of 10% aqueous sodium bisulfate, theorganic layer was separated and the aqueous layer extracted one timewith 5 mL of dichloro-methane. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (25 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 0.040 g (15%) of thetitle compound.

Analysis calculated for C₁₈H₂₂FNO₂S: %C, 64.45; %H, 6.61; %N, 4.81.Found: %C, 64.2; %H, 6.51; %N, 4.02.

Field Desorption Mass Spectrum: M=335.

EXAMPLE 11 N-2-(4-(2-fluorophenyl)phenyl)propyl N′,N′-dimethylsulfamide

A solution of 0.2 g (0.80 mmol) of material from Preparation 6 and 0.13mL (0.95 mmol) of triethylamine in 5 mL of dichloromethane was cooled to0° C. A solution of 0.086 mL (0.80 mmol) of dimethylsulfamoyl chloridein 1 mL of dichloromethane was added dropwise. The ice-bath was removedand the mixture was stirred at ambient temperature for 16 hours. Themixture was washed with 5 mL of 10% aqueous sodium bisulfate, theorganic layer was separated and the aqueous layer extracted one timewith 5 mL of dichloro-methane. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (25 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 0.20 g (74%) of thetitle compound.

Analysis calculated for C₁₇H₂₁FN₂O₂S: %C, 60.69; %H, 6.29; %N, 8.33.Found: %C, 60.42; %H, 6.23; %N, 8.06.

Field Desorption Mass Spectrum: M=336

EXAMPLE 12 N-2-(4-Isopropyl)phenyl)propyl trifluoromethanesulfonamide

A suspension of the product of Preparation 8, 0.30 g (1.40 mmol) indichloromethane (20 ml) was cooled to 0° C. Triethylamine 0.59 ml (4.21mmol) was added to the suspension, followed by trifluoromethanesulfonylchloride 0.16 ml (1.54 mmol). The solution was stirred at 0° C. forthirty minutes then warmed to ambient temperature. The progress of thereaction was monitored by thin layer chromatography. After consumptionof the starting material, the reaction mixture was partitioned betweenwater and dichloromethane. The organic fraction was washed with 0.2Mhydrochloric acid, brine, dried (MgSO₄) and concentrated in vacuo.Chromatography (SiO₂, 30% ethyl acetate/hexanes) gave 0.35 g (81%) ofthe title compound.

Field Desorption Mass Spectrum: M=309.

Analysis for C₁₃H₁₈F₃NO₃S: Theory: C, 50.48; H, 5.86; N, 4.53. Found: C,50.40; H, 5.78; N, 4.74.

EXAMPLE 13 N-2-(4-Isopropylphenyl)propyl 2-propanesulfonamide

A suspension of the product of Preparation 8, 0.30 g, (1.40 mmol) indichloromethane (20 ml) was cooled to 0° C. Triethylamine 0.59 ml (4.21mmol) was added to the suspension, followed by isopropylsulfonylchloride(0.16 ml, 1.54 mmol). The solution was stirred at 0° C. for thirtyminutes then warmed to ambient temperature. The progress of the reactionwas monitored by thin layer chromatography. After consumption of thestarting material, the reaction mixture was partitioned between waterand dichloromethane. The organic fraction was washed with 0.2Mhydrochloric acid, brine, dried over (MgSO₄) and concentrated in vacuo.Chromatography (SiO₂, 30% ethyl acetate/hexanes) gave the title compound0.35 g (81%).

Field Desorption Mass Spectrum: M=283.

Analysis for C₁₃H₁₈F₃NO₃S: Theory: C, 63.57; H, 8.89; N, 4.94. Found: C,63.63; H, 8.90; N, 5.18.

EXAMPLE 14 N-2-(4-Methoxyphenyl)propyl trifluoromethanesulfonamide

A suspension of the product of Preparation 10, 1.00 g (4.96 mmol) indichloromethane (50 ml) was cooled to 0° C. Triethylamine 2.09 ml (14.9mmol) was added to the suspension, followed bytrifluoromethanesulfonyl-chloride 0.58 ml (5.45 mmol). The solution wasstirred at 0° C. for thirty minutes then warmed to ambient temperature.The progress of the reaction was monitored by thin layer chromatography.After consumption of the starting material, the reaction mixture waspartitioned between water and dichloromethane. The organic fraction waswashed with 0.2M hydrochloric acid, brine, dried over magnesium sulfateand concentrated in vacuo. Chromatography (SiO₂, 30% ethylacetate/hexanes) gave the title compound 1.07 g (73%).

Field Desorption Mass Spectrum: M=297.

Analysis for C₁₁H₁₄F₃NO₃S: Theory: C, 44.44; H, 4.75; N, 4.77. Found: C,44.54; H, 4.55; N, 4.80.

EXAMPLE 15 N-2-(4-Cyclopentylphenyl)propyl methanesulfonamide

Condition 1: The product of Example 1, 0.50 g (1.71 mmol) was dissolvedin anhydrous tetrahydrofuran (5 ml) under an atmosphere of nitrogen. Tothis was added tetrakis-(triphenylphosphine)palladium(0) (0.099 g, 0.086mmol) followed by cyclopentyl magnesium bromide (2 M in diethyl ether,2.14 ml, 4.28 mmol). The solution was heated to reflux for 16 hours.Upon cooling the reaction was partitioned between water and diethylether. The aqueous layer was back extracted with diethyl ether twice andthe organic fractions combined. The organic layers were washed withbrine, dried (MgSO₄) and concentrated in vacua. Chromatography (SiO₂,30% ethyl acetate/hexanes) gave the title compound 0.06 g (13%).

Field Desorption Mass Spectrum: M=281.

Analysis for C₁₅H₂₃NO₂S: Theory: C, 64.02; H, 8.24; N, 4.98. Found: C,64.30; H, 8.35; N, 4.84.

Condition 2: Subsequently it has been discovered that the optimalconditions for the above reaction are as follows: The bromide wasdissolved in diethyl ether and cooled to −78° C.[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II)(PdCl₂(dppf)) was added followed by the appropriate alkyl magnesiumreagent. The solution was stirred for an hour then allowed to warm toambient temperature over 2 hours. The work up is the same as inCondition 1 described above.

EXAMPLE 16 N-2-(4-t-butylphenyl)propyl methanesulfonamide

65 mg (0.57 mmol) of methanesulfonyl chloride in dichloromethane (5 mL)was added dropwise to a solution of 100 mg (0.52 mmol) of the product ofPreparation 23 and 60 mg (0.59 mmol) of triethylamine in dichloromethane(15 mL) at ambient temperature under N₂. The reaction mixture wasstirred for 16 hours at ambient temperature. The mixture was thenconcentrated under reduced pressure and the resulting semi-solid wastaken into 25 mL ethyl acetate, washed once with 25 mL H₂O, dried overK₂CO₃, and concentrated under reduced pressure. Recrystallization fromhexane/ethyl acetate 9:1 produced the title compound 65 mg (46%) aswhite crystals.

Analysis calculated for C₁₄H₂₃NO₂S: % C, 62.42; % H, 8.61; % N,5.20.Found % C 62.64; % H, 8.41; % N, 5.19.

Mass Spectrum: M=269.

EXAMPLE 17 N-2-(4-t-butylphenyl)propyl trifluoromethanesulfonamide

The title compound 70 mg (29%) was prepared as an oil following themethod of Example 16, starting from the product of Preparation 23 andusing trifluoromethanesulfonyl chloride.

Analysis calculated for C₁₄H₂₀NO₂SF₃: % C, 52.00; % H, 6.23; % N, 4.33.Found % C, 51.79; % H, 6.20; % N, 4.27. Mass Spectrum: M=323.

EXAMPLE 18 N-2-(4-t-butylphenyl)butyl methanesulfonamide

The title compound, 140 mg (67%) was prepared as an oil following themethod of Example 16, starting from the product of Preparation 24.Purification was achieved by silica gel chromatography(Chromatotron-1000 micron rotor) eluting with a solvent of hexane/ethylacetate 3:1.

Analysis calculated for C₁₅H₂₅NO₂S: % C, 63.57; % H, 8.89; % N, 4.94.Found % C, 63.63, % H, 8.49; % N, 4.93.

Mass Spectrum: M=283.

EXAMPLE 19 N-2-(4-t-butylphenyl)-2-methylpropyltrifluoromethane-sulfonamide

The title compound, 131 mg (40%) was prepared as a crystalline solidfrom hexane/ethyl acetate 19:1 following the method of Example 16,starting from the product of Preparation 25 and usingtrifluoromethanesulfonyl chloride.

Analysis calculated for C₁₅H₂₂NO₂SF₃: % C, 53.40; % H, 6.57; % N, 4.15.Found % C, 53.75; % H, 6.40; % N, 4.02. Mass Spectrum: M=337.

EXAMPLE 20 N-2-(2-naphthyl)propyl trifluoromethanesulfonamide

The title compound was prepared following the method of Example 16,starting from the product of Preparation 26. Purification was achievedby silica gel chromatography (Chromatotron-1000 micron rotor) andeluting with a solvent of hexane/ethyl acetate 19:1 to yield the titlecompound 140 mg (44%) as a solid.

Analysis calculated for C₁₄H₁₄NO₂SF₃: % C, 52.99; % H, 4.45; % N, 4.41.Found: % C, 52.90; % H, 4.42; % N, 4.32.

Mass Spectrum: M=317.

EXAMPLE 21 N-2-(4-t-butylphenyl)butyl trifluoromethanesulfonamide

The title compound was prepared following the method of Example 16,starting from the product of Preparation 24 and usingtrifluoromethanesulfonyl chloride. Purification was achieved by silicagel chromatography (Chromatotron-2000 micron rotor) eluting with asolvent of hexane/ethyl acetate 19:1 to yield the title compound, 187 mg(57%) as an oil.

Analysis calculated for C₁₅H₂₂NO₂SF₃: % C, 53.56; % H, 6.31; % N, 4.12.Found: % C, 53.40; % H, 6.57; % N, 4.15.

Mass Spectrum: M=337.

EXAMPLE 22 N-2-(4-t-butylphenyl)butyl 2-propanesulfonamide

The title compound was prepared following the method of Example 16,starting from the product of Preparation 24 and isopropylsulfonylchloride. Purification was achieved by silica gel chromatography(Chromatotron-2000 micron rotor) eluting with a gradient solvent ofhexane to hexane/ethyl acetate 4:1 producing the title compound 73 mg(32%) as an oil.

Analysis calculated for C₁₇H₂₉NO₂S: % C, 65.55; % H, 9.38; % N, 4.50.Found: % C, 64.65; % H, 8.96; % N, 4.60.

Mass Spectrum: M=311.

EXAMPLE 23 N-2-(4-t-butylphenyl)propyl 2-propanesulfonamide

The title compound was prepared following the method of Example 16,starting from the product of Preparation 23 and isopropylsulfonylchloride. Purification was achieved via silica gel chromatography(Chromatotron-2000 micron rotor) eluting with a solvent of hexane/ethylacetate 4:1 to produce the title compound 111 mg (29%).

Analysis calculated for C₁₆H₂₇NO₂S: % C, 64.61; % H, 9.15; % N, 4.71.Found: % C, 64.53, % H, 8.99; % N, 4.92.

Mass spectrum: M=297.

EXAMPLE 24 N-1-(4-t-butylphenyl)cyclopropylmethyltrifluoromethanesulfonamide

165 mg (0.98 mmol) of trifluoromethylsulfonyl chloride, 100 mg (0.49mmol) of the product of Preparation 30, and 100 mg (0.98 mmol) oftriethylamine were combined in dichloro-methane (15 mL) and reacted asdescribed in Example 16 to yield 164 mg of an oil. This material waspurified via silica gel chromatography eluting with a gradient solventof hexane to hexane/EtOAc 9:1 to yield 100 mg (61%) of the titlecompound as a slowly crystallizing oil. m.p. 82°-84° C. Calculated forC₁₅H₂₀NO₂SF₃: Theory: C, 53.72; H, 6.01; N, 4.18 Found: C, 53.97; H,6.12; N, 4.10.

Mass spectrum: M=335.

EXAMPLE 25 N-1-(4-t-butylphenyl)cyclopropylmethyl 2-propanesulfonamide

140 mg (0.98 mmol) of isopropylsulfonyl chloride, 100 mg (0.49 mmol) ofthe product of Preparation 30, and 100 mg (0.98 mmol) of triethylaminewere combined in dichloromethane (15 mL) and reacted as described inExample 16 to yield 147 mg of an oil. This material was purified viasilica gel chromatography eluting with a gradient solvent ofhexane/EtOAc 19:1 to hexane/EtOAc 1:1 to yield the title compound 33 mg(22%) as a slowly crystallizing oil. m.p. 87°-89.5° C. Calculated forC₁₇H₂₇NO₂S: Theory C, 65.98; H, 8.79; N, 4.53 Found: C, 65.78; H, 9.01;N, 4.35.

EXAMPLE 26 N-2-(4-(4-Methylphenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.4 g (4.7 mmol) of the product of Example 1,1.0 g (7.1 mmol) of 4-methylbenzene-boronic acid, 1.0 g (7.1 mmol) ofpotassium carbonate in 30 mL of toluene, and 10 mL of water was added0.3 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). Themixture was heated to 100° C. for 2 hr, cooled to ambient temperatureand the organic portion was separated. The aqueous portion was extractedthree times with ethyl acetate and the combined organic portions weredried (MgSO₄), filtered and concentrated in vacuo. The residue waschromatographed on silica gel (30% ethyl acetate/hexane) to afford anoff-white solid. The solid was suspended in diethyl ether, filtered anddried in vacuo to afford 0.6 g (43%) of the title compound.

Analysis calculated for C₁₇H₂₁NO₂S: %C, 67.29; %H, 6.98; %N, 4.62.Found: %C, 66.98; %H, 6.96; %N, 4.36.

Field Desorption Mass Spectrum: M=307

EXAMPLE 27 N-2-(4-Bromophenyl)propyl 2-propylsulfonamide

To a suspension of 0.5 g (2.0 mmol) of the product of Preparation 31 in5 mL of dichloromethane was added 0.6 mL (4.0 mmol) of triethylamine.The mixture was cooled to 0° C. and 0.2 mL (2.0 mmol) ofisopropylsulfonyl chloride was added. After stirring at 0° C. for 20min, the mixture was washed once with 10% aqueous sodium bisulfate andthe organic layer was separated. The aqueous layer was extracted threetimes with dichloromethane. The combined organic portions were dried(Na₂SO₄), filtered and concentrated in vacuo. Chromatography on 50 gsilica gel (35% ethyl acetate/hexane) afforded 0.2 g (25%) of the titlecompound.

Analysis calculated for C₁₂H₁₈NO₂SBr: %C, 45.01; %H, 5.67; %N, 4.37.Found: %C, 45.30; %H, 5.92; %N,4.43.

Field Desorption Mass Spectrum: M+1=321

EXAMPLE 28 N-2-(4-(3-thienyl)phenylpropyl 2-propanesulfonamide

A. N-2-(4-(3-thienyl)phenyl)-N-t-butoxycarbonylpropyl amine: To adegassed solution of 8.2 g (26.0 mmol) of material from Preparation 4,4.0 g (31.2 mmol) of thiophene-3-boronic acid and 5.3 g (39.0 mmol) ofpotassium carbonate in 75 mL of dioxane and 25 mL of water was added 1.5g (1.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to ambienttemperature and 200 mL of water and 100 mL of ether was added. Theorganic layer was separated and the aqueous layer was extracted threetimes with 60 mL each of ether. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (500 g ofsilica gel, 10% ethyl acetate/hexane) of the residue afforded 7.8 g(94%) of the title compound.

B. 2-(4-(3-thienyl)phenyl)propylamine trifluoroacetic acid salt: Asolution of 7.8 g (24.6 mmol) of material from Step A in 80 mL 20%trifluoroacetic acid/dichloromethane was stirred at ambient temperaturefor 5 h. The mixture was concentrated in vacuo to afford 8.1 g (100%) ofthe title compound.

C. A solution of 0.5 g (1.5 mmol) of material from Step B and 0.52 mL(3.7 mmol) of triethylamine in 10 mL of dichloro-methane was cooled to0° C. A solution of 0.17 mL (1.5 mmol) of isopropylsulfonyl chloride in1 mL of dichloromethane was added dropwise. The ice-bath was removed andthe mixture was stirred at room temperature for 5 h. The mixture waswashed with 10 mL of 10% aqueous sodium bisulfate, the organic layer wasseparated and the aqueous layer extracted three times with 5 mL ofdichloromethane. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (25 g of silica gel, 35% ethylacetate/-hexane) of the residue afforded 0.100 g (21%) of the titlecompound.

Analysis calculated for C₁₆H₂₁NO₂S₂: %C, 59.41; %H, 6.54; %N, 4.33.Found: %C, 59.34; %H, 6.34; %N, 4.29.

Field Desorption Mass Spectrum: M=323.

EXAMPLE 29 N-2-(4-(3-thienyl)phenylpropyl dimethylsulfamide

A. A solution of 0.5 g (1.5 mmol) of material from Example 28, Step Band 0.52 mL (3.70 mmol) of triethylamine in 10 mL of dichloromethane wascooled to 0° C. A solution of 0.16 mL (1.5 mmol) of dimethylsulfamoylchloride in 1 mL of dichloro-methane was added dropwise. The ice-bathwas removed and the mixture was stirred at ambient temperature for 5 h.The mixture was washed with 10 mL of 10% aqueous sodium bisulfate, theorganic layer was separated and the aqueous layer extracted three timeswith 5 mL of dichloromethane. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. The residue was suspended in 50%ether/hexane and filtered to afford 0.22 g (46%) of the title compound.

Analysis calculated for C₁₅H₂₀N₂O₂S₂: %C, 55.53; %H, 6.21; %N, 8.63.Found: %C, 55.51; %H, 6.21; %N, 8.39.

Field Desorption Mass Spectrum: M=324.

EXAMPLE 30 N-2-(4-Methoxyphenyl)propyl 2-propanesulfonamide

The title product was prepared from the product of Preparation 10 asdescribed in Example 13.

Field Desorption Mass Spectrum: M=271.4

Analysis for C₁₃H₂₁NO₃S: Theory: C, 56.71; H, 8.16; N, 4.86. Found: C,57.54; H, 7.80; N, 5.16.

EXAMPLE 31 N-2-(4-Methylphenyl)propyl) 2-propanesulfonamide

The title compound was prepared from the product of Preparation 33 asdescribed in Example 13.

Field Desorption Mass Spectrum: M=255.2.

Analysis for C₁₃H₂₁NO₂S: Theory: C, 61.14; H, 8.29; N, 5.48. Found: C,61.23; H, 8.35; N, 5.30.

EXAMPLE 32 N-2-(4-Isopropylphenyl)propyl ethanesulfonamide

The title product was prepared from the product of Preparation 8 asdescribed in Example 13 with the exception that ethanesulfonyl chloridewas used instead of isopropylsulfonyl chloride.

Field Desorption Mass Spectrum: M=269.1.

Analysis for C₁₄H₂₃NO₂S: Theory: C, 62.42; H, 8.61; N, 5.20. Found: C,62.68; H, 8.34; N, 5.11.

EXAMPLE 33 N-2-(4-Isopropylphenyl)propyl dimethylsulfamide

The title product was prepared from the product of Preparation 8 asdescribed in Example 13 with the exception that dimethylsulfamoylchloride was used instead of isopropylsulfonyl chloride.

Field Desorption Mass Spectrum: M=349.1.

Analysis for C₁₄H₂₃NO₂S: Theory: C, 55.00; H, 6.35; N, 4.01. Found: C,54.70; H, 6.12; N, 3.82.

EXAMPLE 34 N-2-(4-Isobutylphenyl)propyl 2-propanesulfonamide

The title product was prepared from 2-(4-isobutylphenyl) propyl aminehydrochloride as described in Example 13.

Field Desorption Mass Spectrum: M=297.2

Analysis for C₁₆H₂₇NO₂S: Theory: C, 64.61; H, 9.15; N, 4.71. Found: C,64.84; H, 9.10; N, 4.74.

EXAMPLE 35 N-2-(4-Cyclopentylphenyl)propyl 2-propanesulfonamide

The title product was prepared from ((4-bromo)-2-methylphenethyl)2-propanesulfonamide as described in Example 15, Condition 2.

Field Desorption Mass Spectrum: M=309.3.

Analysis for C₁₇H₂₇NO₂S: Theory: C, 65.98; H, 8.79; N, 4.53. Found: C,66.21; H, 9.04; N, 4.54.

EXAMPLE 36 N-2-(4-Cyclohexylphenyl)propyl 2-propanesulfonamide

The title product was prepared from the product of Example 27 asdescribed in Example 15, Condition 2, with the exception thatcyclohexylmagnesium chloride was used instead of cyclopentylmagnesiumbromide.

Field Desorption Mass Spectrum: M=323.3.

Analysis for C₁₈H₂₉NO₂S: Theory: C, 66.83; H, 9.04; N, 4.33. Found: C,67.00; H, 9.18; N, 4.09.

EXAMPLE 37 N-2-(3-Chloro4-piperidinylphenyl)propyl 2-propanesulfonamide

The title product was prepared from2-(3-chloro4-piperidinylphenyl)propylamine hydrochloride as described inExample 13.

Field Desorption Mass Spectrum: M=358.2

Analysis for C₁₇H₂₇ClN₂O₂S: Theory: C, 56.89; H, 7.58; N, 7.80. Found:C, 57.19; H, 7.68; N, 8.02.

EXAMPLE 38 N-2-(−)-(4-Piperidinylphenyl)propyl) 2-propanesulfonamide

The title product was prepared from(−)-2-(4-piperidinylphenyl)propylamine hydrochloride (Synthesis, 6, 447,1991) as described in Example 13.

Field Desorption Mass Spectrum: M=324.2.

Analysis for C₁₇H₂₈N₂O₂S: Theory: C, 62.93; H,8.70; N, 8.63. Found: C,63.22; H, 8.51; N, 8.49.

EXAMPLE 39 N-2-(+)-((4-Piperidinylphenyl)propyl) 2-propanesulfonamide

The title product was prepared from (+)-2-(4-piperidinylphenyl)propylamine hydrochloride (Synthesis 6, 447, 1991) as describedin Example 13.

Field Desorption Mass Spectrum: M=324.2.

Analysis for C₁₇H₂₈N₂O₂S: Theory: C, 62.93; H, 8.70; N, 8.63. Found: C,62.68; H, 8.45; N, 8.72.

EXAMPLE 40 N-2-(4-Benzyloxyphenyl)propyl) 2-propanesulfonamide

The title compound was prepared from the product of Preparation 35 asdescribed in Example 13.

Field Desorption Mass Spectrum: M=347.2.

Analysis for C₁₉H₂₅NO₃S: Theory: C, 65.68; H, 7.25; N, 4.03. Found: C,65.63; H, 7.31; N, 4.07.

EXAMPLE 41 N-2-(4-Isopropoxyphenyl)propyl 2-propanesulfonamide

The product from Preparation 36 (0.14 g, 0.40 mmol) was dissolved indimethylformamide and sodium hydride (0.018 g, 0.44 mmol) added. After10 minutes, 2-bromopropane (0.054g, 0.44 mmol) was added and thereaction stirred at ambient temperature for 2 hours. The reactionmixture was partitioned between diethyl ether and water. The organicfraction was washed with brine, dried over magnesium sulfate andconcentrated in vacuo. Chromatography (SiO₂, 20% ethyl acetate/hexanes)gave 0.11 g (70%) of the alkylated material. This material was dissolvedin dichloromethane and treated with trifluoroacetic acid at ambienttemperature. The reaction was washed with water, brine, dried overmagnesium sulfate and concentrated in vacuo to yield 0.083 g of thetitle product.

Field Desorption Mass Spectrum: M=299.0.

Analysis for C₁₅H₂₅NO₃S: Theory: C, 60.17; H, 8.42; N, 4.68. Found: C,58.57; H, 8.40; N, 4.31.

EXAMPLE 42 N-2-(4-(2-fluorophenyl)phenyl)propyl 2-methanesulfonamide

A solution of 1.6 g (6.5 mmol) of material from Preparation 6 and 1.2 mL(7.1 mmol) of N,N-diisopropyl-ethylamine in 20 mL of dichloromethane wascooled to 0° C. A solution of 0.51 mL (6.5 mmol) of methanesulfonylchloride in 1 mL of dichloromethane was added dropwise. The ice-bath wasremoved and the mixture was stirred at ambient temperature for 1 hour.The mixture was washed with 20 mL of 10% aqueous sodium bisulfate, theorganic layer was separated and the aqueous layer was extracted threetimes with 5 mL of 1:1 dichloromethane/ether. The combined organics weredried (MgSO₄), filtered and concentrated in vacuo to afford 1.9 g (100%)of the title compound.

Field Desorption Mass Spectrum: M=307

Analysis for C₁₆H_(18F)NO₂S: Theory: C, 62.52; H, 5.90; N, 4.56. Found:C, 64.41; H, 5.99; N, 4.67.

EXAMPLE 43 N-1-methyl-2-(4-bromophenyl)ethyl 2-methanesulfonamide

A solution of 3.0 g (14.0 mmol) of the product of Preparation 38 and 2.1mL (15.4 mmol) of triethylamine in 50 mL of dichloromethane was cooledto 0° C. A solution of 1.1 mL (14.0 mmol) of methanesulfonyl chloride in2 mL of dichloromethane was added dropwise. The mixture was then stirredat 0° C. for 1 hour. The mixture was then washed with 50 mL of 10%aqueous sodium bisulfate, the organic layer was separated and theaqueous layer was extracted three times with 20 mL of diethyl ether. Thecombined organics were dried (MgSO₄), filtered and concentrated invacuo. Chromatography (100 g of silica gel, 35% ethyl acetate/hexane) ofthe residue afforded 1.5 g (37%) of the title compound.

EXAMPLE 44 N-1-methyl-2-(4-(2-fluorophenyl)phenyl)ethyl2-methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of the product of Example 43,1.1 g (7.7 mmol) of the product of Preparation 3 and 1.1 g (7.7 mmol) ofpotassium carbonate in 20 mL of toluene was added 0.3 g (0.2 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 hours. It was then cooled to ambient temperature and 20 mL ofwater were added. The organic layer was separated and the aqueous layerwas extracted three times with 10 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.The residue was suspended in diethyl ether and filtered to afford 0.673g (43%) of the title compound.

Field Desorption Mass Spectrum: M=307

Analysis for C₁₆H₁₈FNO₂S: Theory: C, 62.52; H, 5.90; N, 4.56. Found: C,62.26; H, 5.92; N, 4.49.

EXAMPLE 45 N-2-(4-(4-formylphenyl)phenyl)propyl 2-propanesulfonamide

A degassed solution of 2.4 g (7.5 mmol) of the material from Preparation39, 1.7 g (11.2 mmol) of 4-formylphenylboronic acid, 1.6 g (11.2 mmol)of potassium carbonate and 0.4 g (0.4 mmol) oftetrakis(triphenyl-phosphine)palladium(0) in 33 mL of dioxane and 11 mLof water was heated to 100° C. overnight. The mixture was cooled to roomtemperature, diluted with 20 mL of water, and extracted three times with50 mL each of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (175 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 1.8 g (71%) of thetitle compound.

Analysis calculated for C₁₉H₂₃NO₃S: %C, 66.06; %H, 6.71; %N, 4.05.Found: %C, 66.23; %H, 6.69; %N, 4.11.

Field Desorption Mass Spectrum: M=345

EXAMPLE 46 N-2-(4-(4-(hydroxymethyl)phenyl)phenyl)propyl2-propanesulfonamide

A solution of 0.5 g (1.45 mmol) of the material from Example 45 and0.055 g (1.45 mmol) of sodium borohydride in 5 mL of ethanol was stirredovernight at room temperature, then concentrated in vacuo. The residuewas partitioned between 25 mL of water and 25 mL of ethyl acetate, theorganic layer separated and the aqueous layer extracted three more timeswith 25 mL each of ethyl acetate. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (25 g ofsilica gel, 60% ethyl acetate/hexane) of the residue afforded 1.8 g(71%) of the title compound.

Analysis calculated for C₁₉H₂₅NO₃S: %C, 65.68; %H, 7.25; %N, 4.03.Found: %C, 65.40; %H, 7.40; %N, 4.02.

Field Desorption Mass Spectrum: M=347

EXAMPLE 47 N-2-(4-(2-formylphenyl)phenyl)propyl 2-propanesulfonamide

Prepared as in Example 45, using 8.1 g (25.1 mmol) of the material fromPreparation 39, 4.7 g (31.4 mmol) of 2-formylphenylboronic acid, 5.2 g(37.3 mmol) of potassium carbonate and 1.5 g (1.3 mmol) oftetrakis(triphenyl-phosphine)palladium(0) in 93 mL of dioxane and 24 mLof water. Afforded 7.5 g (86%) of the title compound.

Analysis calculated for C₁₉H₂₃NO₃S: %C, 66.06; %H, 6.71; %N, 4.05.Found: %C, 66.06; %H, 6.70; %N, 4.10.

Field Desorption Mass Spectrum: M=345

EXAMPLE 48 N-2-(4-(2-(hydroxymethyl)phenyl)phenyl)propyl2-propanesulfonamide

Prepared as in Example 46, using 2.0 g (5.8 mmol) of the material fromExample 47 and 0.22 g (5.8 mmol) of sodium borohydride in 5 mL ofethanol. Afforded 1.7 g (84%) of the title compound.

Analysis calculated for C₁₉H₂₅NO₃S: %C, 65.68; %H, 7.25; %N, 4.03.Found: %C, 65.14; %H, 6.73; %N, 3.76.

Field Desorption Mass Spectrum: M=347

EXAMPLE 49 N-2-(4-(4-(2-t-butoxycarbonylamino)ethyl)phenyl)phenylpropyl2-propanesulfonamide

To a solution of 2.0 g (3.8 mmol) of material from Preparation 40 and1.4 g (4.5 mmol) of material from Preparation 41 in 15 mL of toluene wasadded 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine) palladium (0).The mixture was heated to 100° C. for 6.5 hours, cooled to roomtemperature and diluted with 15 mL of ethyl ether. The mixture waswashed once with 15 mL of saturated aqueous potassium fluoride, theorganic layer was separated and the aqueous layer was extracted threetimes with 10 mL each of ethyl ether. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (100 gsilica gel, 30% ethyl acetate/hexane) of the residue affords 0.6 g (35%)of the title compound.

Analysis calculated for C₂₅H₃₆N₂O₄S: %C, 65.19; %H, 7.88; %N, 6.08.Found: %C, 65.29; %H, 7.84; %N, 5.84.

Mass Spectrum: M=460.

EXAMPLE 50 N-2-(4-(4-(2-aminoethyl)phenyl)phenyl)propyl2-propanesulfonamide

A solution of 0.6 g (1.3 mmol) of material from Example 49 in 5 mL of20% trifluoroacetic acid/dichloromethane was stirred at room temperaturefor 1.5 hours. The mixture was concentrated in vacuo and the residue waspartitioned between 10 mL of dichloromethane and 5 mL of 5 N aqueoussodium hydroxide. The organic layer was separated and the aqueous layerwas extracted three times with 5 mL each of dichloromethane. Thecombined organics were dried (Na₂SO₄), filtered and concentrated invacuo. The resulting solid was suspended in hexane, filtered, rinsedonce with hexane and dried in vacuo at ambient temperature to afford 0.4g (88%) of the title compound.

Analysis calculated for C₂₀H₂₈N₂O₂S: %C, 66.63; %H, 7.83; %N, 7.77.Found: %C, 66.93; %H, 7.79; %N, 7.94.

Mass Spectrum: M=360.

EXAMPLE 51 N-2-(4-(4-(2-methanesulfonamido ethyl)phenyl)phenyl)propyl2-propanesulfonamide

To a room temperature solution of 0.1 g (0.3 mmol) of material fromExample 50 and 0.06 mL (0.4 mmol) of triethylamine in 2 mL ofdichloromethane was added 0.03 mL (0.4 mmol) of methanesulfonylchloride. The mixture was stirred at ambient temperature for 16 hours.Chromatography (10 g silica gel, 50% ethyl acetate/hexane) of thereaction mixture afforded 0.1 g (94%) of the title compound.

Analysis calculated for C₂₁H₃₀N₂O₄S₂: %C, 57.51; %H, 6.89; %N, 6.39.Found: %C, 57.90; %H, 6.72; %N, 6.33.

Mass Spectrum: M=438.

EXAMPLE 52 N-2-(4-(4-hydroxymethyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.5 mmol) of material from Example 45 in 5 mLethanol was added 0.06 g (1.5 mmol) of sodium borohydride. The mixturewas stirred at ambient temperature for 16 hours, concentrated in vacuoand partitioned between 10 mL of ethyl acetate and 5 mL of water. Theorganic layer was separated and the aqueous portion was extracted threetimes with 5 mL each of ethyl acetate. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (25 g ofsilica gel, 60% ethyl acetate/hexane) of the residue afforded 0.5 g(98%) of the title compound. Analysis calculated for C₁₉H₂₅NO₃S: %C,65.68; %H, 7.25; %N, 4.03. Found: %C, 65.40; %H, 7.40; %N, 4.02.

Mass Spectrum: M=347.

EXAMPLE 53 N-2-(4-cyanophenyl)propyl 2-propanesulfonamide

A suspension of 10.0 g (31.2 mmol) of material from Preparation 39, 11.2g (124.8 mmol) of copper (I) cyanide and 23.8 g (124.8 mmol) of copper(I) iodide in 230 mL of dry dimethylformamide was heated to 140° C. for16 hours, cooled to ambient temperature and concentrated in vacuo. Theresidue was suspended in 200 mL of ethyl acetate, filtered throughcelite and concentrated in vacuo. Chromatography (500 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 6.4 g (77%) of thetitle compound.

Analysis calculated for C₁₃H₁₈N₂O₂S: %C, 58.62; %H, 6.81; %N, 10.51.Found: %C, 58.44; %H, 6.64; %N, 10.23.

Mass Spectrum: M=266.

EXAMPLE 54 N-2-(4-(5-bromo-[1,2,4]oxadiazol-3-yl)phenyl)propyl2-propanesulfonamide

A suspension of 2.0 g (7.5 mmol) of material from Example 53, 0.8 g (3.8mmol) of material from Preparation 45 and 1.3 g (12.0 mmol) in 3 mL oftoluene was heated to 90° C. for 7 hours, cooled and diluted with 10 mLof ethyl acetate. The mixture was washed once with 10 mL of water, theorganic layer was separated and the aqueous layer was extracted threetimes with 5 mL each of ethyl acetate. The combined organics were dried(MgSO4), filtered and concentrated in vacuo. Chromatography (150 g ofsilica gel, 30% ethyl acetate/hexane) of the residue afforded a solidwhich was recrystallized from ethyl ether to afford 0.06 g (4%) of thetitle compound.

Analysis calculated for C₁₄H₁₈N₂BrO₃S: %C, 43.31; %H, 4.67; %N, 10.82.Found: %C, 43.58; %H, 4.65; %N, 10.76.

Mass Spectrum: M−1=387.

EXAMPLE 55 N-2-(4-(2-furyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g(1.7 mmol) of 2-(tributylstannyl)-furan in 5 mL of dioxane was added 0.1g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixturewas heated to reflux for 16 hours, cooled to ambient temperature anddiluted with 5 mL of ethyl ether. The mixture was washed once with 5 mLof saturated aqueous potassium fluoride, the organic layer was separatedand the aqueous portion was extracted three times with 5 mL each ofethyl ether. The combined organics were dried (MgSO4), filtered andconcentrated in vacuo. Chromatography (25 g of silica gel, 25% ethylacetate/hexane) of the residue afforded a yellow oil which wasrecrystallized from ethyl ether/hexane to afford 0.2 g (51%) of thetitle compound.

Analysis calculated for C₁₆H₂₁NO₃S: %C, 62.51; %H, 6.89; %N, 4.56.Found: %C, 62.73; %H, 6.90; %N, 4.31.

Mass Spectrum: M=307.

EXAMPLE 56N-2-(4-(4-(2-N′,N′-dimethylaminosulfonamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title product was prepared from N,N-dimethylsulfamoyl chloride asdescribed in Example 51.

Analysis calculated for C₂₂H₃₃N₃O₄S₂: %C, 56.50; %H, 7.11; %N, 8.99.Found: %C, 56.21; %H, 7.20; %N, 8.71.

Mass Spectrum: M=467.

EXAMPLE 57 N-2-(4-(2-(4,5-dihydro)thiazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.2 g (0.8 mmol) of material from Example 53 and 0.1 g(1.5 mmol) of 2-aminoethanethiol in 5 mL of ethanol was heated to refluxfor 16 hours, cooled to ambient temperature and concentrated in vacuo.Chromatography (25 g of silica gel, 50% ethyl acetate/hexane) of theresidue afforded 0.2 g (86%) of the title compound.

Analysis calculated for C₁₅H₂₂N₂O₂S₂: %C, 55.18; %H, 6.79; %N, 8.58.Found: %C, 55.03; %H, 6.73; %N, 8.37.

Mass Spectrum: M=326.

EXAMPLE 58 N-2-(4-(4-cyanophenyl)phenyl)propyl 2-proranesulfonamide

To a degassed solution of 4.0 g (12.4 mmol) of material from Example 27,2.0 g (13.6 mmol) of material from Preparation 42 and 1.9 g (13.6 mmol)of potassium carbonate in 73 mL of 75% dioxane/water was added 0.7 g(0.6 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture washeated to 100° C. for 16 hours, cooled to ambient temperature, dilutedwith 30 mL of water and extracted three times with 35 mL each of ethylether. The combined organics were dried (MgSO4), filtered andconcentrated in vacuo. Chromatography (250 g of silica gel, 35% ethylacetate/hexane) of the residue afforded 2.3 g (56%) of the titlecompound as a pale yellow solid. Recrystallization of 0.16 g fromchorobutane afforded 0.12 g of the pure title compound.

Analysis calculated for C₁₉H₂₂N₂O₂S: %C, 66.64; %H, 6.48; %N, 8.18.Found: %C, 66.86; %H, 6.42; %N, 8.09.

Mass Spectrum: M=342.

EXAMPLE 59 N-2-(4-(4-t-butoxycarbonylaminomethyl)-phenyl)phenyl)propyl2-propanesulfonamide

A. N-2-(4-(4-aminomethylphenyl)phenylpropyl 2-propanesulfonamidehydrochloride: A solution of 2.2 g (6.4 mmol) of material from Example58 in 70 mL of ethanol and 3 mL of 1 N hydrochloric acid washydrogenated in the presence of 0.2 g of 5% palladium on carbon atambient temperature and 60 p.s.i. for 16 hours. The mixture was filteredthrough celite and concentrated in vacuo. To the residue was added 4 mLof 1 N hydrochloric acid and the mixture was concentrated in vacuo. Theresidue was dissolved in 10 mL of ethanol and the mixture wasconcentrated in vacuo. The residue was suspended in 50 mL of ethylacetate and stirred for one hour, filtered and dried in vacuo to afford1.7 g (75%) of the title compound.

B. To a suspension of 1.1 g (3.3 mmol) in 10 mL of dichloromethane wasadded 0.5 mL (3.6 mmol) of triethylamine and the mixture was stirred for15 minutes. To the mixture was added 0.7 g (3.3 mmol) of di-tert-butyldicarbonate and the mixture was stirred for 16 hours at ambienttemperature. The mixture was washed once with 5 mL of 10% aqueous sodiumbisulfate, the organic layer was separated and the aqueous layer wasextracted two times with 5mL each of dichloromethane. The combinedorganics were dried (Na₂SO₄), filtered and concentrated in vacuo.Chromatography (75 g of silica gel, 30% ethyl acetate/hexane) of theresidue afforded 0.5 g (32%) of the title compound.

Analysis calculated for C₂₄H₃₄N₂O₄S: %C, 64.55; %H, 7.67; %N, 6.27.Found: %C, 64.70; %H, 7.69; %N, 6.39.

Mass Spectrum: M=446.

EXAMPLE 60 N-2-(4-(4-aminomethyl)phenyl)phenyl)propyl2-propanesulfonamide, trifluoroacetic acid salt

A solution of 0.5 g (1.0 mmol) of material from Example 59 in 5 mL of20% trifluoroacetic acid/dichloromethane was stirred at ambienttemperature for two hours. The mixture was concentrated in vacuodissolved in 5 mL of dichloromethane and washed with 5 mL of saturatedaqueous sodium bicarbonate. The organic layer was separated and theaqueous layer was extracted three times with 5 mL each ofdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. To the residue was added 4 mL dichloromethane andthe resulting precipitate was filtered, rinsed with ethyl ether anddried in vacuo at 60° C. to afford 0.2 g (49%) of the title compound.

Analysis calculated for C₁₉H₂₆N₂O₂S.C₂HO₂F₃: %C, 54.77; %H, 5.91; %N,6.08. Found: %C, 54.70; %H, 5.95; %N, 6.11.

Mass Spectrum: M=346.

EXAMPLE 61 N-2-(4-(2-thienyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Example 27, 0.3 g(2.3 mmol) of thiophene-2-boronic acid and 0.3 g (2.3 mmol) of potassiumcarbonate in 7 mL of dioxane and 2 mL of water was added 0.1 g (0.1mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture washeated to 100° C. for 16 hours cooled to ambient temperature, dilutedwith 5 mL of water and extracted three times with 5 mL each of ethylether. The combined organics were dried (MgSO4), filtered andconcentrated in vacuo. The residue was recrystallized from ethyl ether,filtered and dried in vacuo to afford 0.2 g (47%) of the title compound.

Analysis calculated for C₁₆H₂₁NO₂S₂: %C, 59.41; %H, 6.54; %N, 4.33.Found: %C, 59.36; %H, 6.44; %N, 4.11.

Mass Spectrum: M=323.

EXAMPLE 62N-2-(4-(4-(1-hydroxy-2-methanesulfonamidoethyl)phenyl)phenyl)propyl2-propanesulfonamide

A solution of 0.3 g (0.5 mmol) of material from Preparation 44 (Step D)in 3.5 mL of 14% trifluoroacetic acid/dichloromethane was stirred atambient temperature for four hours. 0.5 mL of trifluoroacetic acid wasadded and the mixture was heated to 50° C. for two hours. The mixturewas cooled to ambient temperature and concentrated in vacuo. The residuewas dissolved in 5 mL of dichloromethane and washed once with 5 mL ofsaturated aqueous sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted three times with 5 mL each ofdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Chromatography (10 g of silica gel, 50% ethylacetate/hexane) of the residue afforded 0.1 g (51%) of the titlecompound.

Analysis calculated for C₂₁H₃₀N₂O₅S₂. 0.05 CHCl₃: %C, 54.89; %H, 6.58;%N, 6.08. Found: %C, 54.66; %H, 6.79; %N, 6.27.

Mass Spectrum: M=454.

EXAMPLE 63 N-2-(4-(5-tetrazolyl)phenyl)propyl 2-propanesulfonamide

0.2 g (0.8 mmol) of material from Example 53 and 0.5 g (1.5 mmol) ofazidotributylstannane were heated to 80° C. for 72 hours. The mixturewas cooled to ambient temperature, 5 mL of a saturated methanolic HClsolution was added, the mixture stirred for 30 minutes and wasconcentrated in vacuo. The residue was dissolved in 10 mL ofacetonitrile and extracted four times with 5 mL each of hexane. Theacetonitrile layer was concentrated in vacuo and the resulting solid wassuspended in 10 mL of ethyl ether, filtered and dried in vacuo at 60° C.to afford 0.2 g (89%) of the title compound.

Analysis calculated for C₁₃H₁₉N₅O₂S: %C, 50.47; %H, 6.19; %N, 22.64.Found: %C, 50.19; %H, 6.11; %N, 22.54.

Mass Spectrum: M+1=310.

EXAMPLE 64 N-2-(4-(5-(2-methyl)tetrazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.1 g (0.3 mmol) of material from Example 63, 0.07 g (0.5mmol) of potassium carbonate and 0.03 mL (0.4 mmol) of methyl iodide in2 mL of N,N-dimethylformamide was heated to 80° C. for 16 hours. Themixture was cooled to ambient temperature, diluted with 10 mL of waterand extracted four times with 5 mL each of dichloromethane. The combinedorganics were dried (Na₂SO₄), filtered and concentrated in vacuo.Chromatography (10 g of silica gel, 25% ethyl acetate/-hexane) of theresidue afforded 0.05 g (48%) of the title compound.

Analysis calculated for C₁₄H₂₁N₅O₂S: %C, 51.99; %H, 6.54; %N, 21.65.Found: %C, 52.28; %H, 6.54; %N, 21.83.

Mass Spectrum: M=323.

EXAMPLE 65 N-2-(4-(2-thiazolyl)phenyl)propyl 2-propanesulfonamide

A solution of 0.7 g (2.1 mmol) of material from Preparation 39, 0.5 g(2.2 mmol) of material from Preparation 46 and 0.1 g (0.1 mmol) oftetrakis-(triphenylphosphine)palladium(0) in 6 mL of dioxane was heatedto 100° C. for 16 hours. The mixture was cooled to ambient temperature,diluted with 10 mL of ethyl ether and washed once with 10 mL ofsaturated aqueous potassium fluoride. The organic layer was separatedand the aqueous layer was extracted three times with 5 mL each of ethylether. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (30 g of silica gel, 45% ethylacetate/hexane) of the residue afforded an oil which was crystallizedfrom ethyl ether, filtered and dried in vacuo at 60° C. to afford 0.3 g(41%) of the title compound.

Analysis calculated for C₁₅H₂₀N₂O₂S₂: %C, 55.53; %H, 6.21; %N, 8.63.Found: %C, 55.75; %H, 6.29; %N, 8.63.

Mass Spectrum: M=324.

EXAMPLE 66N-2-(4-(2-(4S-methoxycarbonvyl4,5-dihydro)thiazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.3 g (0.9 mmol) of material from Example 53, 0.3 g (1.9mmol) of L-cysteine methyl ester hydrochloride and 0.3 mL (1.9 mmol) oftriethylamine in 5 mL of ethanol was heated to reflux for 16 hours. Themixture was cooled to ambient temperature and concentrated in vacuo. Theresidue was dissolved in 5 mL of ethyl acetate and washed once with 5 mLof water. The organic layer was separated and the aqueous layer wasextracted three times with 5 mL each of ethyl acetate. The combinedorganic were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (10 g of silica gel, 45% ethyl acetate/hexane) of theresidue afforded 0.05 g (15%) of the title compound.

Mass Spectrum: M=384.

EXAMPLE 67N-2-(4-(2-(4R-methoxycarbonvyl4,5-dihydro)thiazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.3 g (0.9 mmol) of material from Example 53, 0.2 g (1.4mmol) of D-cysteine methyl ester hydrochloride and 0.2 mL (1.4 mmol) oftriethylamine in 5 mL of ethanol was heated to reflux for 16 hours. Tothe mixture was added 0.16 g (0.9 mmol) of D-cysteine methyl esterhydrochloride and 0.14 mL (0.9 mmol) of triethylamine and reflux wascontinued for 7 hours. The mixture was cooled to ambient temperature andconcentrated in vacuo. The residue was dissolved in 5 mL of ethylacetate and washed once with 5 mL of water. The organic layer wasseparated and the aqueous layer was extracted three times with 5 mL eachof ethyl acetate. The combined organic were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (10 g of silica gel, 45% ethylacetate/hexane) of the residue afforded 0.04 g (11%) of the titlecompound.

Analysis calculated for C₁₇H₂₄N₂O₄S₂: %C, 53.10; %H, 6.29; %N, 7.29.Found: %C, 52.99; %H, 6.35; %N, 7.49.

Mass Spectrum: M=384.

EXAMPLE 68N-(2-(4-(4-(2-(2-propane)sulfonamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.1 g (0.3 mmol) of material from Example 50 and 0.07mL (0.5 mmol) of triethylamine in 1 mL of dichloromethane was added 0.04mL (0.3 mmol) of isopropylsulfonyl chloride. The mixture was stirred atambient temperature for 16 hours. The mixture was washed once with 1.5mL of 10% aqueous sodium bisulfate, the organic layer was separated andthe aqueous layer was extracted two times with 1 mL each ofdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Chromatography (10 g of silica gel, 50% ethylacetate/-hexane) of the residue afforded 0.05 g (39%) of the titlecompound.

Analysis calculated for C₂₃H₃₄N₂O₄S₂: %C, 59.20; %H, 7.34; %N, 6.00.Found: %C, 59.08; %H, 7.33; %N, 5.76.

Mass Spectrum: M=466.

EXAMPLE 69 N-2-(4-(5-formylthien-3-yl)phenyl)propyl 2-propanesulfonamide

To a degassed solution of 0.4 g (0.8 mmol) of material from Preparation40 and 0.09 mL (0.8 mmol) of 4-bromo-2-thiophenecarboxaldehyde in 3 mLof dioxane was added 0.05 g (0.04 mmol) oftetrakis(triphenylphosphine)-palladium(0). The mixture was heated to100° C. for 16 hours, cooled to ambient temperature and diluted with 3mL of ethyl acetate. The mixture was washed once with 3 mL of saturatedaqueous potassium fluoride. The organic layer was separated and theaqueous layer was extracted three times with 3 mL each of ethyl acetate.The combined organics were dried (MgSO₄), filtered and concentrated invacuo. Chromatography (25 g silica gel, 35% ethyl acetate/-hexane) ofthe residue afforded a solid which was suspended in ethyl ether,filtered and dried in vacuo to afford 0.1 g (42%) of the title compound.

Analysis calculated for C₁₇H₂₁NO₃S₂: %C, 58.09; %H, 6.02; %N, 3.99.Found: %C, 58.29; %H, 6.04; %N, 3.71.

Mass Spectrum: M=351.

EXAMPLE 70 N-2-(4-(5-hydroxymethylthien-3-yl)phenyl)propyl2-propanesulfonamide

To solution of 0.09 g (0.3 mmol) of material from Example 69 in 2 mL ofethanol was added 0.01 g (0.3 mmol) of sodium borohydride. The mixturewas stirred at ambient temperature for 16 hours and concentrated invacuo. The residue was partitioned between 5 mL of ethyl acetate and 5mL of water. The organic layer was separated and the aqueous layer wasextracted three times with 3 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (1 g silica gel, 50% ethyl acetate/hexane) of the residueafforded 0.06 g (69%) of the title compound.

Mass Spectrum: M=353.

EXAMPLE 71 N-2-(4-(4-(1-hydroxyethyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.2 g (0.4 mmol) of material from Example 45 in 3 mL oftetrahydrofuran at ambient temperature was added 0.3 mL (0.9 mmol) of a3.0M solution of methylmagnesium bromide in ethyl ether. The mixture wasstirred for 16 hours, diluted with 5 mL of water and extracted fourtimes with 5 mL each of ethyl acetate. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (10 g silicagel, 45% ethyl acetate/hexane) of the residue afforded 0.1 g (74%) ofthe title compound.

Analysis calculated for C₂₀H₂₇NO₃S. 0.2CHCl₃: %C, 62.96; %H, 7.11; %N,3.63. Found: %C, 63.31; %H, 7.02; %N, 3.62.

Mass Spectrum: M=361.

EXAMPLE 72 N-2-(4-(4-(1-hydroxypropyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.3 g (0.7 mmol) of material from Example 45 in 4 mL oftetrahydrofuran at ambient temperature was added 0.5 mL (1.5 mmol) of a3.0M solution of ethylmagnesium bromide in ethyl ether. The mixture wasstirred for 16 hours, diluted with 5 mL of half saturated brine andextracted four times with 5 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (15 g silica gel, 50% ethyl acetate/hexane) of theresidue afforded 0.1 g (42%) of the title compound.

Analysis calculated for C₂₁H₂₉NO₃S: %C, 67.17; %H, 7.78; %N, 3.73.Found: %C, 66.95; %H, 7.69; %N, 3.59.

Mass Spectrum: M=375.

EXAMPLE 73 N-2-(4-4-carboxyphenyl)phenyl)propyl 2-propanesulfonamide

To a degassed solution of 1.0 g (3.1 mmol) of material from Preparation39, 0.8 g (4.7 mmol) of 4-carboxyphenylboronic acid and 0.7 g (4.7 mmol)of potassium carbonate in 20 mL of 75% dioxane/water was added 0.2 g(0.2 mmol) of tetrakis(triphenylphosphine)-palladium(0). The mixture washeated to 100° C. for 16 hours, cooled to ambient temperature anddiluted with 15 mL of 10% aqueous sodium bisulfate. The mixture wasextracted three times with 20 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Recrystallization of the residue from chlorobutane afforded 0.4 g (37%)of the title compound. A 0.1 g sample was recrystallized to afford 0.07g of pure title compound.

Analysis calculated for C₁₉H₂₃NO₄S: %C, 63.14; %H, 6.41; %N, 3.88.Found: %C, 63.25; %H, 6.42; %N, 3.79.

Mass Spectrum: M=361.

EXAMPLE 74 N-2-(4-(4-carbamoylphenyl)phenyl)propyl 2-propanesulfonamide

To a 0° C. solution of 0.3 g (0.9 mmol) of material from Example 73 and0.1 mL (0.9 mmol) of 4-methyl-morpholine in 5 mL of dichloromethane wasadded 0.1 mL (0.9 mmol) of isobutylchloroformate and the mixture wasstirred at 0° C. for 30 minutes. One third of the mixture was added to 2mL of 2.0 M ammonia in methanol at 0° C. and the cooling bath wasremoved. After 20 minutes, the resulting solid was filtered and dried invacuo at 60° C. to afford 0.034 g (33%) of the title compound.

Analysis calculated for C₁₉H₂₄N₂O₃: %C, 63.31; %H, 6.71; %N,7.77. Found:%C, 63.68; %H, 6.85; %N, 7.61.

Mass Spectrum: M=360.

EXAMPLE 75 N-2-(4-(4-methylcarbamoylphenyl)phenyl)propyl2-propanesulfonamide

To a 0° C. solution of 0.9 g (2.4 mmol) of material from Example 73 and0.3 mL (2.5 mmol) of 4-methyl-morpholine in 5 mL of dichloromethane wasadded 0.3 mL (2.5 mmol) of isobutylchloroformate and the mixture wasstirred at 0° C. for 30 minutes. To the mixture was added 10 mL of 40%aqueous methylamine at 0° C. and the cooling bath was removed. After onehour, 10 mL of water was added, the organic layer was separated and theaqueous layer was extracted two times with 5 mL each of dichloromethane.The combined organics were dried (MgSO₄), filtered and concentrated invacuo. Recrystallization from methanol/chlorobutane afforded 0.4 g (44%)of the title compound.

Analysis calculated for C₂₀H₂₆N₂O₃S: %C, 64.14; %H, 7.00; %N, 7.48.Found: %C, 63.97; %H, 6.92; %N, 7.33.

Mass Spectrum: M=374.

EXAMPLE 76 N-2-(4-(4-dimethylcarbamoylphenyl)phenyl)propyl2-propanesulfonamide

To a 0° C. solution of 0.3 g (0.9 mmol) of material from Example 73 and0.1 mL (0.9 mmol) of 4-methyl-morpholine in 5 mL of dichloromethane wasadded 0.1 mL (0.9 mmol) of isobutylchloroformate and the mixture wasstirred at 0° C. for 30 minutes. One third of the mixture was added to 2mL of 2.0 M dimethylamine in tetra-hydrofuran at 0° C. and the coolingbath was removed. After 25 minutes, the mixture was diluted with 5 mL ofethyl acetate and washed once with 5 mL of water. The organic layer wasseparated and the aqueous layer was extracted three times with 2 mL eachof ethyl acetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was crystallized from ethyl ether,filtered and dried in vacuo at 60° C. to afford 0.04 g (36%) of thetitle compound.

Analysis calculated for C₂₁H₂₈N₂O₃S: %C, 64.92; %H, 7.26; %N,7.21.Found: %C, 64.84; %H, 7.19; %N, 6.92.

Mass Spectrum: M=388.

EXAMPLE 77 N-2-(4-(4-acetylphenyl)phenyl)propyl 2-propanesulfonamide

To a degassed solution of 1.0 g (3.1 mmol) of material from Preparation39, 0.8 g (4.7 mmol) of 4-acetylphenylboronic acid and 0.7 g (4.7 mmol)of potassium carbonate in 20 mL of 75% dioxane/water was added 0.2 g(0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture washeated to 100° C. for 4.5 hours, cooled to ambient temperature anddiluted with 15 mL of water. The resulting solid was filtered, dried andrecrystallized from chlorobutane to afford 0.7 g (65%) of the titlecompound.

Analysis calculated for C₂₀H₂₅NO₃S: %C, 66.82; %H, 7.01; %N, 3.90.Found: %C, 66.95; %H, 7.16; %N, 3.63.

Mass Spectrum: M=359.

EXAMPLE 78 N-2-(4-(2-(5-formyl)thienyl)phenyl)propyl2-propanesulfonamide

To a degassed solution of 0.4 g (0.8 mmol) of material from Preparation40 and 0.09 mL (0.8 mmol) of 5-bromo-2-thiophenecarboxaldehyde in 3 mLof dioxane was added 0.05 g (0.04 mmol) oftetrakis(triphenylphosphine)-palladium(0). The mixture was heated to100° C. for 16 hours, 0.04 mL (0.4 mmol) of5-bromo-2-thiophene-carboxaldehyde was added and heating was continuedfor 6 hours. The mixture was cooled to ambient temperature andconcentrated in vacuo. Chromatography (25 g silica gel, 35% ethylacetate/hexane) of the residue afforded a solid which was suspended inethyl ether, filtered and dried in vacuo to afford 0.06 g (24%) of thetitle compound.

Analysis calculated for C₁₇H₂₁NO₃S₂: %C, 58.09; %H, 6.02; %N, 3.99.Found: %C, 58.22; %H, 6.07; %N, 3.69.

Mass Spectrum: M=351.

EXAMPLE 79 N-2-(4-(2-(5-hydroxymethyl)thienyl)phenyl )propyl2-propanesulfonamide

To a solution of 0.03 g (0.08 mmol) of material from Example 78 in 1 mLethanol was added 0.003 g (0.08 mmol) of sodium borohydride. The mixturewas stirred at ambient temperature for 2 hours, concentrated in vacuoand partitioned between 2 mL of ethyl acetate and 2 mL of water. Theorganic layer was separated and the aqueous portion was extracted threetimes with 1 mL each of ethyl acetate. The combined organics were dried(MgSO4), filtered and concentrated in vacuo. Chromatography (1 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 0.02 g(64%) of the title compound.

Analysis calculated for C₁₇H₂₃NO₃S₂. 0.05CHCl₃: %C, 56.97; %H, 6.46; %N,3.90. Found: %C, 57.13; %H, 6.34; %N, 3.75.

Mass Spectrum: M=353.

EXAMPLE 80 N-2-(4-(2-(5-methoxycarbonyl)thiazolyl)phenyl)propyl2-propanesulfonamide

To a 0° C. solution of 2.0 g (5.2 mmol) of material from Example 66 and0.9 mL (5.8 mmol) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in 15 mLdichloromethane was added 0.5 mL (5.8 mmol) of bromotrichloromethanedropwise over 8 minutes. The mixture was stirred at 0° C. for 2 hoursand washed once with 10 mL of saturated aqueous ammonium chloride. Theorganic layer was separated and the aqueous layer was extracted twotimes with 10 mL each of ethyl acetate. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (100 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 1.5 g(76%) of the title compound.

Analysis calculated for C₁₇H₂₂N₂O₄S₂: %C, 53.38; %H, 5.80; %N, 7.32.Found: %C, 53.08; %H, 5.94; %N, 7.18.

Mass Spectrum: M=382.

EXAMPLE 81 N-2-(4-(2-aminophenyl)phenyl)propyl 2-propanesulfonamide

To a degassed solution of 0.5 g (0.9 mmol) of material from Preparation40 and 0.2 g (0.9 mmol) of 2-bromoanitine in 3 mL of toluene was added0.06 g (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0). Themixture was heated to 100° C. for 16 hours whereupon 0.03 g (0.03 mmol)of tetrakis(triphenylphosphine)palladium(0) was added and heating wascontinued for 16 hours. The mixture was cooled to ambient temperatureand chromatographed (25 g silica gel, 35% ethyl acetate/-hexane) toafford an oil which was crystallized from chlorobutane/hexane to afford0.06 g (20%) of the title compound.

Analysis calculated for C₁₈H₂₄N₂O₂S: %C, 65.03; %H, 7.28; %N, 8.43.Found: %C, 65.17; %H, 7.40; %N, 8.29.

Mass Spectrum: M=332.

EXAMPLE 82 N-2-(4-(4-phenyl)phenyl)propyl 2-propanesulfonamide

To a degassed solution of 0.5 g (1.6 mmol) of material from Preparation39, 0.3 g (2.3 mmol) of phenylboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 9 mL of 7: dioxane/water was added 0.09 g (0.08mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture washeated to 100° C. for 16 hours, cooled to ambient temperature anddiluted with 5 mL of water. The mixture was extracted three times with 5mL each of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (25 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 0.4 g (71%) of thetitle compound.

Analysis calculated for C₁₈H₂₃NO₂S: %C, 68.14; %H, 7.30; %N, 4.41.Found: %C, 67.81; %H, 7.23; %N, 4.61.

Mass Spectrum: M=317.

EXAMPLE 83 N-2-(4-(2-(5-carboxy)thiazolyl)phenyl)propyl2-propanesulfonamide

To a solution of 1.4 g (3.7 mmol) of material from Example 80, in 25 mLof 4:1 methanol/tetrahydrofuran was added 4.1 mL (4.1 mmol) of 1 Naqueous sodium hydroxide. After 5 hours was added 1.0 mL (1.0 mmol) of 1N aqueous sodium hydroxide. The mixture stirred for 16 hours and wasconcentrated in vacuo. The residue was dissolved in 25 mL of water andextracted once with ethyl ether. The organic layer was discarded and theaqueous layer was acidified to pH 2 with 10% aqueous sodium bisulfate.The aqueous layer was extracted four times with 25 mL each of ethylacetate and the combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. The resulting solid was suspended in ethyl ether,filtered and dried in vacuo to afford 1.0 g (70%) of the title compound.A 0.2 g sample was recrystallized from methanol/ethyl acetate to afford0.1 g of pure title compound.

Analysis calculated for C₁₆H₂₀N₂O₂S₂: %C, 52.15; %H, 5.47; %N, 7.60.Found: %C, 52.24; %H, 5.40; %N, 7.42.

Mass Spectrum: M=368.

EXAMPLE 84 N-2-(4-(4-(2-cyanoethenyl)phenyl)phenyl propyl2-1propanesulfonamide

To a suspension of 0.4 g (10.4 mmol) of sodium hydride (washed threetimes with hexane) in 2 mL of tetrahydrofuran was added 1.6 mL (10.4mmol) of diethyl cyanomethylphosphonate. The mixture was stirred atambient temperature for 15 minutes. To the mixture was added a solutionof 3.0 g (8.7 mmol) of material from Example 45 in 15 mL oftetrahydrofuran. After stirring for two hours, the mixture was dilutedwith 25 mL of water and extracted three times with 20 mL each of ethylether. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (150 g of silica gel, 35% ethylacetate/hexane) of the residue gave a white solid which was suspended inethyl ether, filtered and dried in vacuo to afford 2.5 g (79%) of thetitle compound.

Analysis calculated for C₂₁H₂₄N₂O₂S: %C, 68.45; %H, 6.56; %N, 7.60.Found: %C, 68.65; %H, 6.49; %N, 7.55.

Mass Spectrum: M=368.

EXAMPLE 85 N-2-(4-(3-(2-bromo)thienyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.1 g (0.3 mmol) of material from Example 28 in 0.5 mLof 1:1 chloroform/acetic acid was added a suspension of 0.06 g (0.3mmol) of N-bromosuccinimide in 1 mL of 1:1 chloroform/acetic acid. Themixture was stirred at ambient temperature for one hour and diluted with1.5 mL of water. The organic layer was separated, washed once with 1 Naqueous sodium hydroxide, dried (MgSO₄), filtered and concentrated invacuo. The residue was dissolved in 1 mL of dichloromethane, filteredthrough a plug of silica gel eluting with 35% ethyl acetate/hexane andconcentrated in vacuo to afford 0.1 g (72%) of the title compound.

Analysis calculated for C₁₆H₂₀NO₂S₂ Br: %C, 47.76; %H, 5.01; %N, 3.48.Found: %C, 48.02; %H, 5.22; %N, 3.48.

Mass Spectrum: M+2=404.

EXAMPLE 86N-2-(4-(4-(2-(N-(t-butoxycarbonyl)methylsulfonamido)ethanoyl)-phenyl)phenyl)propyl2-propanesulfonamide

A.N-(4tri-n-butylstannylphenyl)carbonylmethyl-N-t-butoxycarbonyl-methanesulfonamide.To a degassed solution of 5.0 g (12.7 mmol) of material from Preparation44 (Step B), 7.1 mL (14.0 mmol) of bis(tributyltin) and 2.0 mL (14.0mmol) of triethylamine in 35 mL of toluene was added 0.7 g (0.6 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated toreflux for 16 hours, cooled to ambient temperature and diluted with 35mL of ethyl acetate. The mixture was washed once with 30 mL of 10%aqueous sodium bisulfate, the organic layer was separated and theaqueous layer was extracted three times with 15 mL each of ethylacetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (200 g of silica gel, 5% ethylacetate/hexane) of the residue afforded 2.2 g (28%) of the titlecompound.

Analysis calculated for C₂₆H₄₅NO₅S Sn: %C, 51.84; %H, 7.53; %N, 2.33.Found: %C, 52.12; %H, 7.56; %N, 2.57.

Mass Spectrum: M+2=604.

B. To a degassed solution of 1.1 g (3.5 mmol) of material fromPreparation 39, 2.1 g (3.5 mmol) of material from Step A in 10 mL oftoluene was added 0.2 g (0.2 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated to 92°C. for 16 hours, 0.2 g (0.2 mmol) oftetrakis(triphenylphosphine)palladium(0) was added and heating continuedfor four hours. The mixture was cooled to ambient temperature anddiluted with 5 mL of ethyl acetate. 5 mL of saturated aqueous potassiumfluoride was added and the mixture stirred for one hour. The mixture wasfiltered through diatomaceous earth, the organic layer was separated andthe aqueous layer was extracted three times with 5 mL each of ethylacetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (50 g of silica gel, 40% ethylacetate/hexane) of the residue afforded a tan solid which was suspendedin ethyl ether, filtered and dried in vacuo to afford 0.2 g (10%) of thetitle compound.

Analysis calculated for C₂₆H₃₆N₂O₇S₂: %C, 56.50; %H, 6.57; %N, 5.07.Found: %C, 56.56; %H, 6.73; %N, 5.18.

Mass Spectrum: M=552.

EXAMPLE 87N-2-(4-(4-(2-methanesulfonamido)-ethanoyl)phenyl)phenyl)propyl2-propanesulfonamide

A solution of 0.2 g (0.3 mmol) of material from Example 86 in 2.5 mL of20% trifluoroacetic acid/-dichloromethane was stirred at ambienttemperature for 1.5 hours. The mixture was concentrated in vacuo,dissolved in 5 mL of dichloromethane and washed with 5 mL of saturatedaqueous sodium bicarbonate. The organic layer was separated and theaqueous layer was extracted three times with 5 mL each ofdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Chromatography (10 g of silica gel, 60% ethylacetate/hexane) of the residue afforded 0.1 g (60%) of the titlecompound.

Analysis calculated for C₂₁H₂₈N₂O₅S₂: %C, 55.73; %H, 6.24; %N, 6.19.Found: %C, 55.44; %H, 6.17; %N, 6.15.

Mass Spectrum: M=452.

EXAMPLE 88N-2-(4-(4-(4-(1,1-dioxotetrahydro-1,2-thiazinyl)phenyl)phenyl)propyl2-propanesulfonamide

A solution of 0.1 g (0.4 mmol) of material from Preparation 49 and 0.2 g(0.4 mmol) of material from Preparation 40 in 2 mL of 20%dioxane/toluene was added 4 mg (0.02 mmol) of palladium(II)acetate and 9mg (0.04 mmol) of triphenylphosphine. The mixture was heated to 100° C.for 16 hours and 0.1 g (0.2 mmol) of material from Preparation 40 wasadded. Heating was continued for 8 hours. The mixture was cooled toambient temperature, diluted with 2 mL of ethyl acetate and 1 mL ofsaturated aqueous potassium fluoride was added. After stirring for onehour the organic layer was separated and the aqueous layer was extractedthree times with 1 mL each of ethyl acetate. The combined organics weredried (MgSO₄), filtered and concentrated in vacuo. Chromatography (10 gof silica gel, 40% ethyl acetate/hexane) of the residue afforded 0.04 g(22%) of the title compound.

Analysis calculated for C₂₂H₃₀N₂O₄S₂: %C, 58.64; %H, 6.71; %N, 6.22.Found: %C, 58.34; %H, 6.77; %N, 6.06.

Mass Spectrum: M−1=449.

EXAMPLE 89 N-2-(4-(5-(3-benzyl)tetrazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.2 g (0.7 mmol) of material from Example 63, 0.1 g (1.0mmol) of potassium carbonate and 0.09 mL (0.7 mmol) of benzyl bromide in4 mL of N,N-dimethylformamide was heated to 80° C. for 4 hours. Themixture was cooled to ambient temperature, diluted with 10 mL of waterand extracted four times with 5 mL each of dichloromethane. The combinedorganics were dried (Na₂SO₄), filtered and concentrated in vacuo.Chromatography (20 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.2 g (79%) of the title compound.

Analysis calculated for C₂₀H₂₅N₅O₂S: %C, 60.13; %H, 6.31; %N, 17.53.Found: %C, 60.36; %H, 6.17; %N, 17.71.

Mass Spectrum: M+1=400.

EXAMPLE 90N-2-(4-(2-(4,5-dihydro-4-methoxycarbonyl-5,5-dimethyl)thiazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.3 g (0.9 mmol) of material from Example 53, 0.5 g (2.4mmol) of material from Preparation 50 and 0.3 mL (2.4 mmol) oftriethylamine in 8 mL of ethanol was heated to reflux for 16 hours. Themixture was cooled to ambient temperature and concentrated in vacuo. Theresidue was dissolved in 10 mL of ethyl acetate and washed once with 10mL of water. The organic layer was separated and the aqueous portion wasextracted three times with 5 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (15 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.17 g (43%) of the title compound.

Analysis calculated for C₁₉H₂₈N₂O₄S₂: %C, 55.31; %H, 6.84; %N, 6.79.Found: %C, 55.35; %H, 6.95; %N, 6.64.

Mass Spectrum: M=412.

EXAMPLE 91 N-2-(4-(5-(2-ethyl)tetrazolyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared from the product of Example 63 asdescribed in Example 64 with the exception that iodoethane was usedinstead of iodomethane.

Analysis calculated for C₁₅H₂₃N₅O₂S: %C, 53.39; %H, 6.87; %N, 20.75.Found: %C, 53.49; %H, 6.89; %N, 20.45.

Mass Spectrum: M+1=338.

EXAMPLE 92 N-2-(4-(5-(2-(2-propyl))tetrazolyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared from the product of Example 63 asdescribed in Example 64 with the exception that 2-iodopropane was usedinstead of iodomethane.

Analysis calculated for C₁₆H₂₅N₅O₂S: %C, 54.68; %H, 7.17; %N, 19.93.Found: %C, 54.78; %H, 6.93; %N, 19.76.

Mass Spectrum: M+1=352.

EXAMPLE 93 N-2-(4-(5-(2-prop-3-enyl)tetrazolyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared from the product of Example 63 asdescribed in Example 64 with the exception that allyl bromide was usedinstead of iodomethane.

Analysis calculated for C₁₆H₂₃N₅O₂S: %C, 54.99; %H, 6.63; %N, 20.04.Found: %C, 54.99; %H, 6.40; %N, 19.77.

Mass Spectrum: M+1=350.

EXAMPLE 94 N-2-(4-(4-aminophenyl)phenyl)propyl 2-propanesulfonamide

A. N-2-(4-(4-t-butoxycarbonylaminophenyl)phenyl)propyl2-propane-sulfonamide: A degassed solution of 0.9 g (2.9 mmol) ofmaterial from Example 39, 1.4 g (2.8 mmol) of material from Preparation51 and 0.2 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium(0) in10 mL of toluene was heated to reflux for 5 hours. The mixture wascooled to ambient temperature and concentrated in vacuo. Chromatography(100 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded0.15 g (12%) of the title compound.

Mass Spectrum: M=432.

B. A solution of 0.2 g (0.5 mmol) of material from Step A in 2.5 mL of20% trifluoroacetic acid/-dichloromethane was stirred at ambienttemperature for two hours. The mixture was concentrated in vacuo,dissolved in 2 mL of dichloromethane and washed once with 1 mL ofsaturated aqueous sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted three times with 1 mL each ofdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was crystallized fromchlorobutane/hexane to afford 0.03 g (20%) of the title compound.

Analysis calculated for C₁₈H₂₄N₂O₂S: %C, 65.03; %H, 7.28; %N, 8.43.Found: %C, 65.11; %H, 7.52; %N, 8.23.

Mass Spectrum: M=350.

EXAMPLE 95 N-2-(4-(3-furyl)phenyl propyl 2-propanesulfonamide

To a solution of 0.8 g (2.6 mmol) of material from Preparation 39 and1.0 g (2.9 mmol) of 3-(tributyl-stannyl)furan in 10 mL of dioxane wasadded 0.2 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). Themixture was heated to reflux for 4 hours, cooled to ambient temperatureand diluted with 10 mL of water. The mixture was extracted three timeswith 10 mL each of ethyl ether. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (25 g ofsilica gel, 25% ethyl acetate/hexane) of the residue afforded a solidwhich was suspended in hexane, filtered and dried in vacuo to afford 0.3g (42%) of the title compound.

Analysis calculated for C₁₆H₂₁NO₃S: %C, 62.51; %H, 6.89; %N, 4.56.Found: %C, 62.64; %H, 6.92; %N, 4.69.

Mass Spectrum: M=307.

EXAMPLE 96 N-2-(4-(2-(4-hydroxymethyl)thiazolyl)phenyl)propyl2-propanesulfonamide

To a 0° C. solution of 0.8 g (2.0 mmol) of material from Example 83 in 6mL of tetrahydrofuran was added 0.4 mL (4.1 mmol) of 10 Mboranedimethylsulfide. The mixture was stirred at 0° C. for 30 minutesand allowed to warm to ambient temperature for 16 hours. To the mixturewas slowly added 3 mL of saturated aqueous sodium bicarbonate. Themixture was diluted with 10 mL of water and extracted four times with 10mL each of ethyl acetate. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. The residue was filtered through 5 gof silica gel and concentrated in vacuo. Chromatography (2 g of silicagel, 50% ethyl acetate/hexane) of the residue afforded 0.03 g (4%) ofthe title compound.

Analysis calculated for C₁₆H₂₂N₂O₃S_(2.) 0.05 CHCl₃: %C, 53.48; %H,6.17; %N, 7.77. Found: %C, 53.31; %H, 6.46; %N, 7.93.

Mass Spectrum: M=354.

EXAMPLE 97 N-2-(4-(4-fluorophenyl)phenyl)propyl methanesulfonamide

To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1,1.1 g (7.7 mmol) of potassium carbonate and 1.1 g (7.7 mmol) of4-fluorobenzeneboronic acid in 30 mL of toluene was added 0.2 g (0.3mmol) of dichlorobis(triphenylphosphine)palladium (II). The mixture washeated to 100° C. for 16 hours and cooled to ambient temperature. Themixture was diluted with 20 mL of ethyl acetate, filtered throughdiatomaceous earth and concentrated in vacuo. Chromatography (50 g ofsilica gel, 30% ethyl acetate/hexane) of the residue afforded a whitesolid which was suspended in ethyl ether, filtered and recrystallizedfrom chlorobutane to afford 0.2 g (12%) of the title compound.

Field Desorption Mass Spectrum: M=307.

EXAMPLE 98 N-2-(4-(2,3-difluorophenyl)phenyl)propyl methanesulfonamide

To a solution of 0.4 g (0.8 mmol) of material from Preparation 52, 0.2 g(0.8 mmol) of 2,3-difluorophenyl trifluoromethanesulfonate, 0.1 g (2.3mmol) of lithium chloride in 5 mL of toluene was added 0.03 g (0.04mmol) of dichlorobis(triphenylphosphine)palladium (II). The mixture washeated to 100° C. for 16 hours and cooled to ambient temperature. Themixture was diluted with 5 mL of ethyl acetate and washed with 5 mL ofwater. The organic layer was separated and the aqueous layer wasextracted three times with 5 mL each of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (50 g of silica gel, 25% ethyl acetate/hexane) of theresidue afforded an oil which was crystallized from diethyl ether toafford 0.1 g (37%) of the title compound.

Analysis calculated for C₁₆H₁₇NO₂SF₂: %C, 59.06; %H, 5.27; %N, 4.30.Found: %C, 59.05; %H, 5.14; %N, 4.08.

Field Desorption Mass Spectrum: M=325.

EXAMPLE 99 N-2-(4-bromophenyl)propyl trifluoromethanesulfonamide

The title compound was prepared from the product of Preparation 2 asdescribed in Preparation 39 with the exception thattrifluoromethanesulfonyl chloride was used instead of isopropylsulfonylchloride.

Analysis calculated for C₁₀H₁₁NO₂SBrF₃: %C, 34.70; %H, 3.20; %N, 4.05.Found: %C, 34.95; %H, 3.32; %N, 4.00.

Field Desorption Mass Spectrum: M+1=347.

EXAMPLE 100 N-2-(4-(2-formylphenyl)phenylpropyl methanesulfonamide

The title compound was prepared from the product of Example 1 asdescribed in Example 97 with the exception that 2-formylbenzeneboronicacid was used instead of 4-fluorbenzeneboronic acid andtetrakis(triphenyl-phosphine)palladium (0) was used instead ofdichlorobis-(triphenylphosphine)palladium (II).

Analysis calculated for C₁₇H₁₉NO₃S: %C, 64.33; %H, 6.03; %N, 4.41.Found: %C, 64.13; %H, 5.90; %N, 4.40.

Field Desorption Mass Spectrum: M=317.

EXAMPLE 101 N-2-(4-(2-methylphenyl)phenyl)propyl methanesulfonamide

The title compound was prepared from the product of Example 1 asdescribed in Example 100 with the exception that 2-methylbenzeneboronicacid was used instead of 2-formylbenzeneboronic and 10 mL of water wasadded to the reaction mixture.

Analysis calculated for C₁₇H₂₁NO₂S: %C, 67.29; %H, 6.98; %N, 4.62.Found: %C, 67.11; %H, 7.18; %N, 4.53.

Field Desorption Mass Spectrum: M=303.

EXAMPLE 102 N-2-(4-(4-methoxyphenyl)phenyl)propyl methanesulfonamide

The title compound was prepared from the product of Example 1 asdescribed in Example 6 with the exception that 4-methoxybenzeneboronicacid was used instead of 2-methoxybenzeneboronic acid.

Analysis calculated for C₁₇H₂₁NO₃S: %C, 63.92; %H, 6.63; %N, 4.39.Found: %C, 63.92; %H, 6.50; %N, 4.18.

Field Desorption Mass Spectrum: M=319.

EXAMPLE 103 N-2-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide

To a 0° C. solution of 3.1 g (14.4 mmol) of material from Preparation 53(Step B) and 4.8 g (31.7 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in50 mL of dichloromethane was added a solution of 2.8 g (15.8 mmol) ofmaterial from Preparation 54 in 10 mL of dichloromethane. The mixturewas stirred at 0° C. for 30 minutes, the cooling bath was removed andthe mixture stirred for one hour. The reaction mixture was washed oncewith 30 mL of 10% aqueous sodium bisulfate. The organic layer wasseparated and the aqueous layer was extracted three times with 10 mLeach of dichloromethane. The combined organics were dried (Na₂SO₄),filtered and concentrated in vacuo. Chromatography (300 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 1.0 g (22%) of thetitle compound.

Analysis calculated for C₁₆H₁₉NO₂S₂: %C, 59.78; %H, 5.96; %N, 4.36.Found: %C, 59.90; %H, 6.10; %N, 4.26.

Field Desorption Mass Spectrum: M+1=322.

EXAMPLE 104 N-2-(4-(hydroxyiminoyl)phenyl)propyl 2-propanesulfonamide

A solution of 0.5 g (1.9 mmol) of material from Preparation 43 and 0.14g (2.0 mmol) of hydroxylamine hydrochloride in 6 mL of ethyl alcohol washeated to reflux for 18 h. The mixture was cooled and concentrated invacuo. The residue was partitioned between 5 mL of water and 5 mL ofethyl acetate. The organic layer was separated and the aqueous layer wasextracted two times with 5 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuoto afforded 0.4 g (74%) of the title compound.

Analysis calculated for C₁₃H₂₀N₂O₃S: %C, 54.91; %H, 7.09; %N, 9.85.Found: %C, 56.04; %H, 6.82; %N, 10.43.

Field Desorption Mass Spectrum: M=284.

EXAMPLE 105 N-2-(4-(3-(5-hydroxymethyl)isoxazolyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.3 g (1.0 mmol) of material from Example 104 and 0.1 g(2.0 mmol) of propargyl alcohol and 0.3 g (3.0 mmol) of potassiumbicarbonate in 3 mL of ethyl acetate and 1 drop of water was added 0.1 g(1.0 mmol) of N-chlorosuccinimide. The mixture was stirred at roomtemperature for 18 hr and then 3 mL of water was added. The organiclayer was separated and the aqueous layer was extracted three times with3 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (12 g ofsilica gel, 50% ethyl acetate/hexane) of the residue afforded 0.037 g(11%) of the title compound.

Analysis calculated for C₁₆H₂₂N₂O₄S: %C, 56.79; %H, 6.55; %N, 8.28.Found: %C, 51.97; %H, 5.93; %N, 10.96.

Field Desorption Mass Spectrum: M=338.

EXAMPLE 106 N-2-(4-(3-(5-methoxycarbonyl)isoxazolyl)phenyl)propyl2-propanesulfonamide

A. N-2-(4-(1-hydroxy-2-chloroiminoyl)phenyl)propyl 2-propanesulfonamide:To a solution of 1.0 g (3.5 mmol) of material from Example 104 in 10 mLN,N-dimethylformamide was added 0.5 g (3.5 mmol) of N-chlorosuccinimidein small solid portions. The solution was stirred at room temperaturefor 3 h. The mixture was poured into 40 mL of ice and the aqueous layerwas extracted three times with 10 mL each of ether. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo toafford 1.25 g (100%) of the title compound.

B. To a solution of 0.5 g (1.0 mmol) of material from Example 106A and0.3 g (3.1 mmol) of methyl propiolate in 3 mL of ethyl acetate and 1drop of water was added 0.5 g (4.7 mmol) of potassium bicarbonate. Themixture was stirred at room temperature for 18 hr and then 3 mL of waterwas added. The organic layer was separated and the aqueous layer wasextracted three times with 3 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (25 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.34 g (51%) of the title compound.

Analysis calculated for C₁₇H₂₂N₂O₅S: %C, 55.72; %H, 6.05; %N, 7.64.Found: %C, 55.95; %H, 6.24; %N, 7.37.

Field Desorption Mass Spectrum: M=366.

EXAMPLE 107 N-2-(4-(3-(5-carboxy)isoxazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.3 g (0.8 mmol) of material from Example 106B in 3 mL ofmethyl alcohol and 1 mL (1 mmol) 1N sodium hydroxide was heated at 50°C. for 18 h. To the mixture was added 1 mL (1 mmol) 1N sodium hydroxideand the mixture was heated at 50° C. for 7 h. The mixture was cooled andconcentrated in vacuo. The residue was partitioned between 3 mL of waterand 3 mL of ether. The organic layer was separated and the aqueous layerwas washed three times with 3 mL each of ether. The aqueous layer wasacidified to pH=1 with conc. hydrochloric acid. The aqueous layer wasextracted three times with 3 mL each of ether. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo toafforded 0.11 g (39%) of the title compound.

Analysis calculated for C₁₆H₂₀N₂O₅S: %C, 54.53; %H, 5.72; %N, 7.95.Found: %C, 55.80; %H, 5.27; %N, 7.74.

Field Desorption Mass Spectrum: M=352.

EXAMPLE 108 N-2-(4-(3-(5-trimethylsilyl)isoxazolyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Example 106A and 0.3g (3.1 mmol) of (trimethylsilyl)acetylene in 3 mL of ethyl acetate and 1drop of water was added 0.5 g (4.7 mmol) of potassium bicarbonate. Themixture was stirred at room temperature for 18 hr and then 3 mL of waterwas added. The organic layer was separated and the aqueous layer wasextracted three times with 3 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (25 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.36 g (59%) of the title compound.

Analysis calculated for C₁₈H₂₈N₂O₃SSi: %C, 56.81; %H, 7.42; %N, 7.36.Found: %C, 57.63; %H, 7.41; %N, 7.52.

Field Desorption Mass Spectrum: M=380.

EXAMPLE 109 N-2-(4-(3-(5-acetyl)isoxazolyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.07 g (0.2 mmol) of material from Example 106A and0.029 g (0.4 mmol) of 3-butyn-2-one in 3 mL of ethyl acetate and 1 dropof water was added 0.066 g (0.6 mmol) of potassium bicarbonate. Themixture was stirred at room temperature for 18 hr and then 3 mL of waterwas added. The organic layer was separated and the aqueous layer wasextracted three times with 3 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (12 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.04 g (57%) of the title compound.

Analysis calculated for C₁₇H₂₂N₂O₄S: %C, 58.27; %H, 6.33; %N, 7.99.Found: %C, 59.08; %H, 6.29; %N, 7.36.

Field Desorption Mass Spectrum: M=350.

EXAMPLE 110 N-2-(4-(3-(5-(N′-methylcarbamoyl))-isoxazolyl)phenyl)propyl2-propanesulfonamide

A solution of 0.1 g (0.28 mmol) of material from Example 107 and 0.03 g(0.3 mmol) N-methylmorpholine in 2 mL of dichloromethane was cooled to0° C. A solution of 0.033 mL (0.3 mmol) of isobutylchloroformate in 1 mLof dichloromethane was added and the mixture was stirred at 0° C. for 30min. The mixture was poured into 2 mL 40% methylamine and water at 0° C.and stirred for 30 min. The organic layer was separated and the aqueouslayer was extracted three times with 3 mL each of ethyl acetate. Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. Chromatography (12 g of silica gel, 50% ethyl acetate/hexane)of the residue afforded 0.04 g (39%) of the title compound.

Analysis calculated for C₁₇H₂₃N₃O₄S: %C, 55.87; %H, 6.34; %N, 11.50.Found: %C, 55.97; %H, 6.28; %N, 11.20.

Field Desorption Mass Spectrum: M=365.

EXAMPLE 111 N-2-(4-(3-isoxazolyl)phenyl)propyl 2-propanesulfonamide

A solution of 0.3 g (0.79 mmol) of material from Example 108 and 0.079mL of conc. ammonium hydroxide was heated at 100° C. for 2 h. To themixture was added 2 drops of conc. ammonium hydroxide and the mixturewas heated at 100° C. for 18 h. The mixture was cooled and partitionedbetween 5 mL of water and 5 mL of ether. The organic layer was separatedand the aqueous layer was extracted three times with 5 mL each of ether.The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (12 g of silica gel, 35% ethylacetate/hexane) of the residue afforded 0.038 g (16%) of the titlecompound.

Analysis calculated for C₁₅H₂₀N₂O₃S: %C, 58.42; %H, 6.54; %N, 9.08.Found: %C, 58.28; %H, 6.67; %N, 8.78.

Field Desorption Mass Spectrum: M=308.

EXAMPLE 112 N-2-(4-(3-(5-(2-hydroxy)ethyl)isoxazolyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.58 g (1.8 mmol) of material from Example 106A and0.25 g (3.6 mmol) of 3-butyn-1-ol in 3 mL of ethyl acetate and 1 drop ofwater was added 0.54 g (5.4 mmol) of potassium bicarbonate. The mixturewas stirred at room temperature for 18 hr and then 3 drops of3-butyn-1-ol was added and stirred for 2 hr and then 3 mL of water wasadded. The organic layer was separated and the aqueous layer wasextracted three times with 3 mL each of ethyl acetate. The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (25 g of silica gel, 75% ethyl acetate/hexane) of theresidue afforded 0.24 g (38%) of the title compound.

Analysis calculated for C₁₇H₂₄N₂O₄S: %C, 57.93; %H, 6.86; %N, 7.95.Found: %C, 58.23; %H, 6.99; %N, 8.14.

Field Desorption Mass Spectrum: M=352.

EXAMPLE 113 N-2-(4-(5-(3-bromo)isoxazolyl)phenyl)propyl2-propanesulfonamide

A. N-2-(4-ethynylphenyl)propyl 2-propanesulfonamide: To a solution of2.0 g (6.2 mmol) of material from Preparation 39 and 2.0 g (6.2 mmol) oftri-n-butylstannylethyne in 20 mL of toluene was added 0.36 g (0.3 mmol)of tetrakis(triphenylphosphine)palladium(0). The mixture was heated at90 ° C. for 18 h. The mixture was cooled and filtered throughdiatomaceous earth and rinsed with 20 mL ethyl acetate and concentratedin vacuo. Chromatography (100 g of silica gel, 35% ethyl acetate/hexane)of the residue afforded 0.3 g (18%) of the title compound.

B. To a solution of 0.3 g (1.1 mmol) of material from Example 113A and0.1 g (0.5 mmol) of material from Preparation 45 in 2 mL of ethylacetate and 1 drop of water was added 0.17 g (0.7 mmol) of potassiumbicarbonate. The mixture was stirred at room temperature for 18 hr andthen 0.1 g (0.5 mmol) of material from Preparation 45 was added andstirred for 5 hr and then 2 mL of water was added. The organic layer wasseparated and dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (12 g of silica gel, 35% ethyl acetate/hexane) of theresidue afforded 0.1 g (23%) of the title compound.

Analysis calculated for C₁₅H₁₉BrN₂O₃S: %C, 46.52; %H, 4.94; %N, 7.23.Found: %C, 46.73; %H, 5.00; %N, 6.94.

Field Desorption Mass Spectrum: M−1=386.

EXAMPLE 114 N-2-(4-(2-pyridyl)phenyl)propyl 2-propanesulfonamide

To a solution of 4.3 g (13.4 mmol) of material from Preparation 39 and4.9 g (13.4 mmol) of 2-(tri-n-butylstannyl)pyridine in 10 mL of toluenewas added 0.78 g (0.67 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 h. Then 0.025 g (0.03 mmol) ofbis(triphenylphosphine)palladium(II) chloride was added and the mixturewas heated at 90° C. for 18 h. The mixture was cooled and concentratedin vacuo. Chromatography (400 g of silica gel, 50% ethyl acetate/hexane)of the residue afforded 4.3 g (98%) of the title compound.

Analysis calculated for C₁₇H₂₂N₂O₂S*0.5H₂O: %C, 62.35; %H, 7.08; %N,8.55. Found: %C, 62.05; %H, 6.78; %N, 8.23.

Field Desorption Mass Spectrum: M=318.

EXAMPLE 115 N-2-(4-(4-pyridyl)phenyl)propyl 2-propanesulfonamide

To a solution of 1.0 g (3.1 mmol) of material from Preparation 39 and1.1 g (3.1 mmol) of 4-(tri-n-butylstannyl)pyridine in 10 mL of dioxanewas added 0.072 g (0.062 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 h. Then 0.1 g (0.08 mmol) oftetrakis(triphenylphosphine)palladium(0) and 0.5 g (1.5 mmol) of4-(tri-n-butylstannyl)pyridine was added and the mixture was heated at90° C. for 18 h. The mixture was cooled and filtered throughdiatomaceous earth and rinsed with 10 mL ethyl acetate. The organic wasdried (MgSO₄), filtered and concentrated in vacuo. The residue wassuspended in 10 mL of dichloromethane and the solid was filtered andwashed with 10 mL of hexane to afforded 0.24 g (24%) of the titlecompound.

Analysis calculated for C₁₇H₂₂N₂O₂S: %C, 64.12; %H, 6.96; %N, 8.80.Found: %C, 63.90; %H, 6.71; %N, 8.93.

Field Desorption Mass Spectrum: M=318.

EXAMPLE 116 N-2-(4-(3-pyridyl)phenyl)propyl 2-propanesulfonamide

To a solution of 1.0 g (3.1 mmol) of material from Preparation 39 and1.1 g (3.1 mmol) of 3-(tri-n-butylstannyl)pyridine in 10 mL of toluenewas added 0.072 g (0.062 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 h. Then 0.1 g (0.08 mmol) oftetrakis(triphenylphosphine)palladium(0) and 0.5 g (1.5 mmol) of3-(tri-n-butylstannyl)pyridine was added and the mixture was heated at90° C. for 18 h. The mixture was cooled and filtered throughdiatomaceous earth and rinsed with 10 mL ethyl acetate. The filtrate wasconcentrated in vacuo. Chromatography (75 g of silica gel, 75% ethylacetate/hexane) of the residue afforded 0.43 g (44%) of the titlecompound.

Analysis calculated for C₁₇H₂₂N₂O₂S*0.25H₂O: %C, 63.23; %H, 7.02; %N,8.67. Found: %C, 63.31; %H, 7.04; %N, 8.01.

Field Desorption Mass Spectrum: M=318.

EXAMPLE 117 N-2-(4-(5-pyrimidinyl)phenyl)propyl 2-propanesulfonamide

A. 5-(tri-n-butylstannyl)pyrimidine: A solution of 19.6 mL (31.4 mmol)1.6M n-butyllithium in 100 mL of ether was cooled to −100° C. and asolution of 5 g (31.4 mmol) of 5-bromopyrimidine in 20 mL of ether wasadded dropwise. The mixture was stirred at −78° C. for 30 min then 8.5mL (31.4 mmol) of tri-n-butylstannyl chloride in 20 mL of ether wasadded dropwise. The mixture was stirred for 30 min and then 100 mL ofwater was added. The organic layer was separated and the aqueous layerwas extracted three times with 30 mL each of ether. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Chromatography (250 g of silica gel, 50% ethyl acetate/hexane) of theresidue afforded 3.3 g (28%) of the title compound.

B. To a solution of 1.4 g (4.4 mmol) of material from Preparation 39 and3.3 g (8.9 mmol) of material from Example 117A in 15 mL of dioxane wasadded 0.25 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). Themixture was heated at 90° C. for 18 h. The mixture was cooled andconcentrated in vacuo. The residue was suspended in 10 mL ofacetonitrile and the solid was filtered and washed with 5 mL ofacetonitrile to afforded 0.06 g (4%) of the title compound.

Analysis calculated for C₁₆H₂₁ N₃O₂S: %C, 60.16; %H, 6.63; %N, 13.15.Found: %C, 60.18; %H, 6.62; %N, 13.00.

Field Desorption Mass Spectrum: M=319.

EXAMPLE 118 N-2-(4-(3-thienyl)phenyl)ethyl 2-propanesulfonamide

To a solution of 1.0 g (3.3 mmol) of material from Preparation 47, 0.5 g(3.9 mmol) of thiophene-3-boronic acid and 0.7 g (4.9 mmol) of potassiumcarbonate in 8 mL of dioxane and 2 mL of water was added 0.18 g (0.16mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture washeated at 90° C. for 18 h. The mixture was cooled to room temperatureand 10 mL of water and 10 mL of ether was added. The organic layer wasseparated and the aqueous layer was extracted three times with 5 mL eachof ether. The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (50 g of silica gel, 35% ethylacetate/hexane) of the residue afforded 0.6 g (59%) of the titlecompound.

Analysis calculated for C₁₅H₁₉NO₂S₂: %C, 58.22; %H, 6.19; %N, 4.53.Found: %C, 58.30; %H, 5.96; %N, 4.48.

Field Desorption Mass Spectrum: M=309.

EXAMPLE 119 N-2-(4-(4-formylphenyl)phenyl)ethyl 2-propanesulfonamide

To a solution of 4.0 g (13.3 mmol) of material from Preparation 47, 2.3g (15.7 mmol) of 4-formyl-benzene-boronic acid and 2.7 g (19.6 mmol) ofpotassium carbonate in 32 mL of dioxane and 8 mL of water was added 0.7g (0.6 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 5 h. The mixture was cooled to room temperatureand 40 mL of water and 40 mL of ether was added. The organic layer wasseparated and the aqueous layer was extracted three times with 20 mLeach of ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (200 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 3.6 g (83%) of thetitle compound.

Analysis calculated for C₁₈H₂₁ NO₃S: %C, 65.23; %H, 6.39; %N, 4.23.Found: %C, 65.38; %H, 6.43; %N, 4.05.

Field Desorption Mass Spectrum: M=331.

EXAMPLE 120 N-2-(4-(4-hydroxymethylphenyl)phenyl)ethyl2-propanesulfonamide

To a solution of 0.5 g (1.5 mmol) of material from Example 119 in 20 mLof ethyl alcohol was added 0.056 g (1.5 mmol) of sodium borohydride. Themixture was stirred at ambient temperature for 2 hr and then 10 mL ofethyl acetate and 10 mL of water was added. The organic layer wasseparated and the aqueous layer was extracted two times with 5 mL eachof ethyl acetate. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo to afford 0.5 g (100%) of the titlecompound.

Analysis calculated for C₁₈H₂₃NO₃S: %C, 64.84; %H, 6.95; %N, 4.20.Found: %C, 64.74; %H, 6.92; %N, 4.36.

Field Desorption Mass Spectrum: M=333.

EXAMPLE 121 N-2-(4-(4-N′-(2-propanesulfonylanilino))phenyl)ethyl2-propanesulfonamide

A. 4-Bromo-N-(t-butoxycarbonyl)aniline: To a solution of 6.0 g (34.9mmol) of 4-bromoaniline in 110 mL of tetrahydrofuran was added 70 mL (70mmol) 1N sodium bis(trimethylsilyl)amide. The mixture was stirred for 15min and 7.6 g (34.9 mmol) of di-tert-butyl dicarbonate was added. Themixture was stirred for 18 hr and then concentrated in vacuo. Theresidue was partitioned between 120 mL of 10% aqueous sodium bisulfateand 120 mL of ethyl acetate. The organic layer was separated and washedtwo times with 50 mL each of brine. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (250 g of silica gel,10% ethyl acetate/hexane) of the residue afforded 5.4 g (57%) of thetitle compound.

B.N-2-(4-(4-N′-t-butoxycarbonylaminophenyl)phenyl)t-butoxycarbonyl)propylamine:To a solution of 1.75 g (3.4 mmol) of material from Preparation 48 and1.0 g (3.4 mmol) of material from Example 121A in 10 mL of toluene wasadded 0.2 g (0.17 mmol) of tetrakis(triphenylphosphine)palladium(0). Themixture was heated at 100° C. for 18 h. The mixture was cooled and 10 mLof water was added. The organic layer was separated and the aqueouslayer was extracted three times with 5 mL each of ethyl acetate. Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. Chromatography (100 g of silica gel, 35% ethyl acetate/hexane)of the residue afforded 0.2 g (14%) of the title compound.

C. A solution of 0.2 g (0.48 mmol) of material from Example 121B in 4 mLof dichloromethane and 1 mL of trifluoroacetic acid was stirred atambient temperature for 3 h. The mixture was concentrated in vacuo andthe residue was dissolved in 5 mL dichloromethane and 0.15 mL (1.0 mmol)of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. The solution was cooledto 0° C. and a solution of 0.06 mL (0.5 mmol) of isopropylsulfonylchloride in 1 mL of dichloromethane was added. The ice-bath was removedand the mixture was stirred at ambient temperature for 4 h. The mixturewas washed with 5 mL of 1N aqueous hydrochloric acid, the organic layerwas separated and the aqueous layer extracted three times with 5 mL ofethyl acetate. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (12 g of silica gel, 50% ethylacetate/-hexane) of the residue afforded 0.005 g (2%) of the titlecompound.

Field Desorption Mass Spectrum: M=424.

EXAMPLE 122 N-2-(4-(4-cyanophenyl)phenyl)ethyl 2-propanesulfonamide

To a solution of 1.7 g (3.4 mmol) of material from Preparation 48 and0.6 g (3.4 mmol) of 4-bromobenzonitrile in 10 mL of toluene was added0.2 g (0.17 mmol) of tetrakis(triphenylphosphine)palladium(0). Themixture was heated at 100° C. for 18 h. The mixture was cooled and thesolid was filtered and rinsed with 10 mL hexane to afforded 0.4 g (36%)of the title compound.

Analysis calculated for C₁₈H₂₀N₂O₂S: %C, 65.83; %H, 6.14; %N, 8.53.Found: %C, 65.61; %H, 5.87; %N, 8.44.

Field Desorption Mass Spectrum: M=328.

EXAMPLE 123 N-2-(4-(4-N′,N′-diethylaminophenyl)phenyl)propyl2-propanesulfonamide

A. 4-N,N-diethylaminobenzeneboronic acid: A solution of 10 g (43.8 mmol)of 4-bromo-N,N-diethylaniline in 150 mL of tetrahydrofuran was cooled to−78° C. and 30 mL (48.2 mmol) of 1.6M n-butyllithium was added dropwise.The mixture was stirred at −78° C. for 60 min then 15.2 mL (65.7 mmol)of triisopropyl borate was added dropwise and stirring was continued for60 min. The cooling bath was removed and then 75 mL of water and SNhydrochloric acid was added until pH=6 and stirring was continued for 18h. The aqueous layer was separated and the organic layer was extractedtwo times with 25 mL each of 1N sodium hydroxide. The combined aqueousextracts were acidified with conc. hydrochloric acid to pH=7. Theresulting solid was filtered and washed with 20 mL methyl alcohol to 2.8g (33%) of the title compound.

B. To a solution of 0.5 g (1.6 mmol) of material from Preparation 39,0.36 g (1.9 mmol) of material from Example 123A and 0.33 g (2.4 mmol) ofpotassium carbonate in 4 mL of dioxane and 1 mL of water was added 0.09g (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 10 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with5 mL each of ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (25 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 0.38 g (61%) of thetitle compound.

Analysis calculated for C₂₂H₃₂N₂O₂S: %C, 68.00; %H, 8.30; %N, 7.21.Found: %C, 67.70; %H, 8.52; %N, 6.98.

Field Desorption Mass Spectrum: M=388.

EXAMPLE 124 N-2-(4-(2-fluorophenyl)phenyl)propyl1-chloromethanesulfonamide

A solution of 0.4 g (1.7 mmol) of material from Preparation 6 and 0.27mL (1.9 mmol) of triethylamine in 10 mL of dichloromethane was cooled to0° C. A solution of 0.15 mL (1.7 mmol) of methanesulfonyl chloride in 1mL of dichloromethane was added. The ice-bath was removed and themixture was stirred at room temperature for 3 h. The mixture was washedwith 10 mL of 10% aqueous sodium bisulfate, the organic layer wasseparated and the aqueous layer extracted three times with 5 mL of 1:1dichloromethane/ether. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo to afford 0.60 g (100%) of the titlecompound.

Analysis calculated for C₁₆H₁₇CIFNO₂S: %C, 56.22; %H, 5.01; %N, 4.10.Found: %C, 56.55; %H, 5.27; %N, 4.10.

Field Desorption Mass Spectrum: M=341.

EXAMPLE 125N-2-(4-(4-(1-(2-(2-propane)sulfonylamino)propyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 1.3 g (2.5 mmol) of material from Preparation 40 and0.65 g (5.0 mmol) of 3-chloro-6-methyl pyridazine in 10 mL of toluenewas added 0.14 g (0.12 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 h. The mixture was cooled and filtered through diatomaceousearth and rinsed with 10 mL ethyl acetate. The filtrate was concentratedin vacuo. Chromatography (50 g of silica gel,50% ethyl acetate/hexane)of the residue afforded 0.20 g (33%) of the title compound.

Analysis calculated for C₂₄H₃₆N₂O₄S: %C, 59.97; %H, 7.55; %N, 5.83.Found: %C, 59.67; %H, 7.55; %N, 5.97.

Field Desorption Mass Spectrum: M−1=479.

EXAMPLE 126N-2-(4-(4-(1-(2-(2-propane)sulfonylamino)-ethyl)phenyl)phenyl)ethyl2-propanesulfonamide

To a solution of 1.5 g (4.9 mmol) of material from Preparation 47, 0.8 g(2.4 mmol) of hexamethyiditin, and 0.6 g (14.7 mmol) of lithium chloridein 20 mL of dioxane was added 0.1 g (0.1 mmol) oftetrakis(triphenylphosphine)palladium(0). The mixture was heated at 90°C. for 18 h. The mixture was cooled and filtered through diatomaceousearth and rinsed with 10 mL ethyl acetate. The filtrate was washed onetime with 10 mL of water and dried (MgSO₄), filtered and concentrated invacuo. Chromatography (75 g of silica gel, 50% ethyl acetate/hexane) ofthe residue afforded 0.054 g (2.5%) of the title compound.

Analysis calculated for C₂₂H₃₂N₂O₄S₂: %C, 58.38; %H, 7.13; %N, 6.19.Found: %C, 58.54; %H, 7.08; %N, 5.92.

Field Desorption Mass Spectrum: M=452.

EXAMPLE 127 N-2-(4-(4-(1-(2-cyano)ethenyl)phenyl)phenyl)ethyl2-pronanesulfonamide

To a solution of 1.5 g (8.4 mmol) of diethyl cyanomethyl phosphonate in15 mL tetrahydrofuran was added 8.4 mL (8.4 mmol) 1M sodiumbis(trimethylsilyl)amide. The mixture was stirred at ambient temperaturefor 30 min and then a solution of material from Example 119 in 5 mL oftetrahydrofuran was added. The mixture was stirred for 1 hr and waswashed with 20 mL of water. The organic layer was separated and theaqueous layer extracted three times with 5 mL of ethyl acetate. Thecombined organics were dried MgSO₄), filtered and concentrated in vacuo.The residue was suspended in 5 mL dichloromethane and the resultingsolid was filtered to afford 1.2 g (56%) of the title compound. Thefiltrate was concentrated in vacuo. Chromatography (100 g of silica gel,50% ethyl acetate/hexane) of the residue afforded an additional 0.5 g(23%) of the title compound.

Analysis calculated for C₂₀H₂₂N₂O₂S: %C, 67.77; %H, 6.26; %N, 7.90.Found: %C, 67.50; %H, 6.21; %N, 7.73.

Field Desorption Mass Spectrum: M=354.

EXAMPLE 128 N-2-(4-(4-(1-(3-amino)propyl)phenyl)phenyl)ethyl2-propanesulfonamide hydrochloride

A solution of 0.47 g (1.3 mmol) of material from Example 127 and 0.32 g5% palladium on carbon in 75 mL ethyl alcohol and 3 mL 5N hydrochloricacid was hydrogenated in a Parr shaker at 60 psi hydrogen and 50° C. for18 h. The mixture was filtered and concentrated in vacuo. The residuewas suspended in 10 mL 1N hydrochloric acid and filtered.Recrystallization from acetonitrile and methyl alcohol afforded 0.1 g(20%) of the title compound.

Analysis calculated for C₂₀H₂₉N₂O₂S*0.85HCl: %C, 61.20; %H, 7.67; %N,7.14. Found: %C, 61.06; %H, 7.70; %N, 6.91.

Field Desorption Mass Spectrum: M−1=360.

EXAMPLE 129N-2-(4-(4-(1-(3-(2-propane)sulfonylamino)-propyl)phenyl)phenyl)ethyl2-propanesulfonamide

To a solution of 0.09 g (0.2 mmol) of material from Example 128 and 0.07mL (0.5 mmol) of triethylamine in 5 mL of dichloromethane was added0.025 mL (0.2 mmol) of isopropyl sulfonyl chloride. The mixture wasstirred at room temperature for 8 h. The mixture was washed with 5 mL of1N hydrochloric acid, the organic layer was separated and the aqueouslayer extracted one time with 5 mL of ethyl acetate. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo toafford 0.050 g (53%) of the title compound.

Analysis calculated for C₂₃H₃₄N₂O₄S₂*0.5CHCl₃: %C, 53.62; %H, 6.61; %N,5.32. Found: %C, 53.18; %H, 6.78; %N, 4.97.

Field Desorption Mass Spectrum: M=466.

EXAMPLE 130 N-2-(4-(3-thienyl)phenyl)propyl ethenesulfonamide

To a solution of 0.21 g (0.9 mmol) of material from Preparation 53B and0.15 mL (1.0 mmol) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in 5 mL ofdichloromethane was added 0.10 mL (1.0 mmol) of2-chloro-1-ethanesulfonyl chloride. The mixture was stirred at roomtemperature for 4 h. The mixture was washed with 5 mL of 1N hydrochloricacid, the organic layer was separated and the aqueous layer extractedthree times with 5 mL of ether. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (10 g ofsilica gel, 25% ethyl acetate/hexane) of the residue afforded 0.2 g(71%) of the title compound.

Analysis calculated for C₁₅H₁₇NO₂S₂*0.2CHCl₃: %C, 55.10; %H, 5.23; %N,4.22. Found: %C, 55.40; %H, 5.10; %N, 4.20.

Field Desorption Mass Spectrum: M−1=306.

EXAMPLE 131 N-2-(4-(3-thienyl)phenyl)propyl ethanesulfonamide

A solution of 0.024 g (0.078 mmol) of material from Example 130 and 5 mg5% palladium on carbon in 5 mL ethyl acetate was degassed three timesunder a hydrogen balloon and stirred at room temperature for 4 h. Themixture was filtered and concentrated in vacuo. The residue wasrecrystallized from ether and hexane to afford 0.024 g (99%) of thetitle compound.

Analysis calculated for C₁₅H₁₉NO₂S₂: %C, 58.22; %H, 6.19; %N, 4.53.Found: %C, 58.63; %H, 5.71; %N, 4.32

Field Desorption Mass Spectrum: M+1=310.

EXAMPLE 132 N-2-(4-(3-acetylphenyl)phenyl)propyl 2-propanesulfonamide

To a solution of 3.2 g (10.2 mmol) of material from Preparation 39, 2.0g (12.2 mmol) of 3-acetylbenzeneboronic acid and 2.1 g (15.2 mmol) ofpotassium carbonate in 28 mL of dioxane and 7 mL of water was added 0.59g (0.51 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 30 mL of water and 30 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with10 mL each of ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (150 g of silica gel,35% ethyl acetate/hexane) of the residue afforded 2.4 g (66%) of thetitle compound.

Analysis calculated for C₂₀H₂₅NO₃S: %C, 66.82; %H, 7.01; %N, 3.89.Found: %C, 66.38; %H, 6.96; %N, 3.73.

Field Desorption Mass Spectrum: M=359.

EXAMPLE 133 N-2-(4-(3-(1-hydroxyethyl)phenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.4 mmol) of material from Example 132 in 5 mLof ethyl alcohol was added 0.05 g (1.4 mmol) of sodium borohydride. Themixture was stirred at ambient temperature for 2 hr, concentrated invacuo and then 10 mL of ethyl acetate and 10 mL of water was added. Theorganic layer was separated and the aqueous layer was extracted threetimes with 5 mL each of ethyl acetate. The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(40 g of silica gel, 50% ethyl acetate/hexane) of the residue afforded0.3 g (65%) of the title compound.

Analysis calculated for C₂₀H₂₇NO₃S: %C, 66.40; %H, 7.53; %N, 3.87.Found: %C, 66.56; %H, 7.65; %N, 3.92.

Field Desorption Mass Spectrum: M=361.

EXAMPLE 134 N-2-(4-(2-benzothienyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.5 mmol) of material from Preparation 39, 0.3 g(1.9 mmol) of benzo[b]thiophene-2-boronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 4 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether and 10 mL ethyl acetatewas added. The mixture was concentrated in vacuo and the residue wasdissolved in 10 mL of ethyl acetate and washed with 10 mL of brine. Theorganic layer was separated and dried (MgSO₄), filtered and concentratedin vacuo. Chromatography (50 g of silica gel, 35% ethyl acetate/hexane)of the residue afforded 0.08 g (14%) of the title compound.

Analysis calculated for C₂₀H₂₃NO₂S₂*0.1 CHCl₃: %C, 62.40; %H, 6.07; %N,3.63. Found: %C, 62.63; %H, 6.04; %N, 3.63.

Field Desorption Mass Spectrum: M=373.

EXAMPLE 135 N-2-(4-(3,4-dichlorophenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.4 g(1.9 mmol) of 3,4-dichlorobenzeneboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with5 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (75 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 0.52 g(86%) of the title compound. A second chromatography (40 g of silicagel, 35% ethyl acetate/hexane) of the title compound afforded 0.25 g(41%) of the title compound.

Analysis calculated for C₁₈H₂₁Cl₂NO₂S: %C, 55.95; %H, 5.48; %N, 3.62.Found: %C, 56.22; %H, 5.28; %N, 3.56.

Field Desorption Mass Spectrum: M−1=385.

EXAMPLE 136 N-2-(4-(4-methylphenyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.25g (1.9 mmol) of 4-methylbenzeneboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with5 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (30 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 0.42 g(82%) of the title compound. A second chromatography (25 g of silicagel, 35% ethyl acetate/hexane) of the title compound afforded 0.24 g(46%) of the title compound.

Analysis calculated for C₁₉H₂₅NO₂S: %C, 68.80; %H, 7.60; %N, 4.20.Found: %C, 69.11; %H, 7.70; %N, 4.10.

Field Desorption Mass Spectrum: M=331.

EXAMPLE 137 N-2-(4-(4-chlorophenyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.29g (1.9 mmol) of 4-chlorobenzeneboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with3 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (35 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 0.36 g ofthe title compound. The compound was recrystallized to purity with etherto afford 0.36 g (65%) of the title compound.

Analysis calculated for C₁₈H₂₂CINO₂S: %C, 61.40; %H, 6.30; %N, 3.98.Found: %C, 61.48; %H, 6.11; %N, 3.62.

Field Desorption Mass Spectrum: M=351.

EXAMPLE 138 N-2-(4-(2-methylphenyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.25g (1.9 mmol) of 2-methylbenzeneboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with4 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (30 g ofsilica gel, 30% ethyl acetate/hexane) of the residue afforded 0.35 g(68%) of the title compound.

Analysis calculated for C₁₉H₂₅NO₂S: %C, 68.8; %H, 7.60; %N, 4.20. Found:%C, 68.82; %H, 7.75; %N, 4.23.

Field Desorption Mass Spectrum: M=331.

EXAMPLE 139 N-2-(4-(3,5-dichlorophenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.36g (1.9 mmol) of 3,5-dichlorobenzeneboronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 hr and then 0.36 g (1.9 mmol) of3,5-dichlorobenzeneboronic acid was added. The mixture was heated at 90°C. for another 18 h. The mixture was cooled to room temperature and 10mL of water and 10 mL of ether was added. The organic layer wasseparated and the aqueous layer was extracted three times with 5 mL eachof ethyl acetate. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Chromatography (35 g of silica gel,10% ethyl acetate/toluene) of the residue afforded 0.36 g (60%) of thetitle compound.

Analysis calculated for C₁₈H₂₁NCl₂O₂S: %C, 55.90; %H, 5.50; %N, 3.60.Found: %C, 56.22; %H, 5.50; %N, 3.39.

Field Desorption Mass Spectrum: M−1=385.

EXAMPLE 140 N-2-(4-(4-trifluoromethylphenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.35g (1.9 mmol) of 4-trifluoromethylbenzeneboronic acid and 0.3 g (2.3mmol) of potassium carbonate in 5 mL of dioxane and 1 mL of water wasadded 0.09 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0).The mixture was heated at 90° C. for 18 h. The mixture was cooled toroom temperature and 5 mL of water and 5 mL of ether was added. Theorganic layer was separated and the aqueous layer was extracted threetimes with 4 mL each of ethyl acetate. The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(50 g of silica gel, 20% ethyl acetate/hexane) of the residue afforded0.40 g (67%) of the title compound.

Analysis calculated for C₁₉H₂₂F₃NO₂S: %C, 59.20; %H, 5.75; %N, 3.60.Found: %C, 59.14; %H, 5.67; %N, 3.34.

Field Desorption Mass Spectrum: M=385.

EXAMPLE 141 N-2-(4-(3-trifluoromethylphenyl)phenyl)propyl2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.35g (1.9 mmol) of 3-trifluoromethylbenzeneboronic acid and 0.3 g (2.3mmol) of potassium carbonate in 5 mL of dioxane and 1 mL of water wasadded 0.09 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0).The mixture was heated at 90° C. for 18 h. The mixture was cooled toroom temperature and 5 mL of water and 5 mL of ether was added. Theorganic layer was separated and the aqueous layer was extracted threetimes with 4 mL each of ethyl acetate. The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(50 g of silica gel, 20% ethyl acetate/hexane) of the residue afforded0.44 g (73%) of the title compound.

Analysis calculated for C₁₉H₂₂F₃NO₂S: %C, 59.20; %H, 5.75; %N, 3.60.Found: %C, 59.20; %H, 5.72; %N, 3.62.

Field Desorption Mass Spectrum: M =385.

EXAMPLE 142 N-2-(4-(3-nitrophenyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.5 g (1.6 mmol) of material from Preparation 39, 0.31g (1.9 mmol) of 3-nitrobenzene-boronic acid and 0.3 g (2.3 mmol) ofpotassium carbonate in 5 mL of dioxane and 1 mL of water was added 0.09g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixturewas heated at 90° C. for 18 h. The mixture was cooled to roomtemperature and 5 mL of water and 5 mL of ether was added. The organiclayer was separated and the aqueous layer was extracted three times with4 mL each of ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (50 g ofsilica gel, 35% ethyl acetate/hexane) of the residue afforded 0.40 g(71%) of the title compound.

Analysis calculated for C₁₈H₂₂N₂O₄S: %C, 59.60; %H, 6.12; %N, 7.73.Found: %C, 59.59; %H, 6.07; %N, 7.74.

Field Desorption Mass Spectrum: M=362.

EXAMPLE 143 N-2-(4-(3-thienyl)phenyl)propyl1-(2-methyl)-propanesulfonamide

A. Isobutylsulfonyl chloride: A solution of diisobutyldisulfide 13 g (73mmol) in 100 mL of water is cooled to 0° C. Chlorine gas was bubbledthrough the aqueous solution until a yellow solution persists and thennitrogen gas was bubbled through for 15 min. The reaction mixture wasdiluted with 100 mL of ether and the organic layer was separated and theaqueous layer extracted three times with 30 mL of ether. The combinedorganics were dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was distilled to afford 12 g (52%) of the title compound.

B. To a solution of 0.5 g (2.3 mmol) of material from Preparation 53Band 0.42 mL (3.0 mmol) of triethyl amine in 10 mL of tetrahydrofuran wasadded 0.47 g (3.0 mmol) of material from Example 143A. The mixture wasstirred at room temperature for 18 h. The mixture was washed with 20 mLof 1N hydrochloric acid, the organic layer was separated and the aqueouslayer extracted three times with 5 mL of ether. The combined organicswere dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(25 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded0.6 g (77%) of the title compound.

Analysis calculated for C₁₇H₂₃NO₂S₂: %C, 60.50; %H, 6.87; %N, 4.15.Found: %C, 60.30; %H, 6.88; %N, 4.07.

Field Desorption Mass Spectrum: M=337.

EXAMPLE 144 N-2-(4-(2-benzothiazoly)phenyl)propyl 2-propanesulfonamide

To a solution of 0.4 g (0.7 mmol) of material from Preparation 40 and0.13 g (0.7 mmol) of 2-chlorobenzothiazole in 5 mL of xylene was added0.016 g (0.02 mmol) of dichlorobis(triphenylphosphine)palladium (II).The mixture was heated at 120° C. for 18 hr and to the mixture was added0.010 g (0.02 mmol) of dichlorobis(triphenylphosphine)palladium (II) andthe mixture was heated at 120° C. for 5 h. The mixture was cooled and 20mL of saturated potassium fluoride was added and the mixture was stirredfor 1 h. The mixture was filtered and the organic layer was removed,dried (MgSO₄), filtered and concentrated in vacuo. Chromatography (25 gof silica gel, 25% ethyl acetate/hexane) of the residue afforded 0.03 g(11%) of the title compound.

Analysis calculated for C₁₉H₂₂N₂O₂S₂: %C, 60.93; %H, 5.92; %N, 7.48.Found: %C, 61.24; %H, 6.05; %N, 7.04.

Field Desorption Mass Spectrum: M=374.

EXAMPLE 145 N-2-(4-(2-fluorophenyl)phenyl)propyl2-methoxyethanesulfonamide

A solution of 0.5 g (1.6 mmol) of material from Example 8 in 5 mL of 2Mammonia in methyl alcohol was stirred at room temperature for 18 h. Tothe solution was added 2 mL of concentrated ammonium hydroxide andstirring was continued for 5 h. The mixture was concentrated in vacuo.Chromatography (25 g of silica gel, 50% ethyl acetate/hexane with 2%methyl alcohol) of the residue afforded 0.03 g (5%) of the titlecompound.

Analysis calculated for C₁₈H₂₂FNO₃S: %C, 61.52; %H, 6.31; %N, 3.99.Found: %C, 65.02; %H, 6.17; %N, 4.06.

Field Desorption Mass Spectrum: M=351.

EXAMPLE 146 N-2-(4-(2-fluorophenyl)phenyl)ethyltrifluoromethanesulfonamide

A solution of 1.0 g (3.0 mmol) of material from Example 7C and 1.0 mL(7.6 mmol) of triethyl amine in 10 mL of dichloromethane was cooled to0° C. and 0.32 mL (3.0 mmol) of trifluoromethanesulfonyl chloride wasadded. The mixture was stirred at 0° C. for 1 h. The mixture was washedwith 10 mL of 10% sodium bisulfate, the organic layer was separated andthe aqueous layer extracted three times with 10 mL of dichloromethane.The combined organics were dried (MgSO₄), filtered and concentrated invacuo to afford 0.45 g (43%) of the title compound.

Analysis calculated for C₁₅H₁₃F₄NO₂: %C, 51.87; %H, 3.77; %N, 4.03.Found: %C, 53.45; %H, 3.91; %N, 4.15.

Field Desorption Mass Spectrum: M=347.

EXAMPLE 147 N-2-(4-(2-fluorophenyl)phenyl)propyltrifluoromethanesulfonamide

A stock solution of 0.53 g (2.3 mmol) of material from Preparation 6 in26 mL of chloroform was prepared and 1 mL was removed and added to a 4mL teflon capped vial. To the vial was added 0.038 g (0.13 mmol) ofpoly(4-vinylpipridine) 2% crosslinked resin and 11.5 mL (0.11 mmol)trifluoromethanesulfonyl chloride. The vial was shaken at roomtemperature for 24 hr and then 0.040 g (0.8 mmol) ofaminomethylpoly-styrene was added and the vial was shaken for 8 h. Thereaction mixture was filtered through a cotton plug and the filtrate wasconcentrated in vacuo to afford the title compound. NMR was consistentwith the proposed compound.

¹H NMR 300 MH₂ (CDCl₃) 67 =1.3(d)

EXAMPLE 148 N-2-(4-(2-fluorophenyl)phenyl)propyltrifluoroethanesulfonamide

The title compound was prepared following the method of Example 147 andusing 12.2 mL (0.11 mmol) 2,2,2-trifluoroethanesulfonyl chloride. NMRwas consistent with the proposed compound.

¹H NMR (CDCl₃) δ=3.9(m)

EXAMPLE 149 N-2-(4-(2-fluorophenyl)phenyl)propyl benzenesulfonamide

The title compound was prepared following the method of Example 147 andusing 14.0 mL (0.11 mmol) benzenesulfonyl chloride. NMR was consistentwith the proposed compound.

Electrospray Mass Spectrum: M+1=370.

EXAMPLE 150 N-2-(4-(2-fluorophenyl)phenyl)propyl4-fluorobenzenesulfonamide

The title compound was prepared following the method of Example 147 andusing 21 mg (0.11 mmol) 4-fluorobenzenesulfonyl chloride. NMR wasconsistent with the proposed compound.

¹H NMR (CDCl₃) δ=4.3(m)

EXAMPLE 151N-2-(4-(4-(2-(ethanesulfonylamino)ethyl)-phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 7.6 mL (0.11 mmol) ethanesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=451.

EXAMPLE 152N-2-(4-(4-(2-(1-propanesulfonylamino)ethyl)-phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 9.0 mL (0.11 mmol) 1-propanesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=465.

EXAMPLE 153N-2-(4-(4-(2-(1-butanesulfonylamino)ethyl)-phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 10.4 mL (0.11 mmol) 1-butanesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=479.

EXAMPLE 154N-2-(4-(1-(2-(1S-10-camphorsulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 20 mg(0.11 mmol) 1S-10-camphorsulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=573.

EXAMPLE 155N-2-(4-(1-(2-(1R-10-camphorsulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 20 mg (0.11 mmol) 1R-10-camphorsulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=573.

EXAMPLE 156N-2-(4-(1-(2-(2-methoxycarbonylethane-sulfonylamino)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 15 mg (0.11 mmol) 2-carbomethoxyethane-sulfonyl chloride.NMR was consistent with the proposed compound.

Electrospray Mass Spectrum: [M+H₂O]=528.

EXAMPLE 157N-2-(4-(1-(2-(2-trifluoroethane-sulfonylamino)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 8.8 mL (0.11 mmol) 2,2,2-trifluoro-ethanesulfonylchloride. NMR was consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=505.

EXAMPLE 158N-2-(4-(1-(2-(benzenesulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 14 mg (0.11 mmol) benzenesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=499.

EXAMPLE 159N-2-(4-(1-(2-(benzylsulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 15 mg (0.11 mmol) a-toluenesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=513.

EXAMPLE 160N-2-(4-(1-(2-(cyclohexanesulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 15 mg (0.11 mmol) cyclohexanesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=505.

EXAMPLE 161N-2-(4-(4-(2-(2-fluorobenzenesulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 15 mg (0.11 mmol) 2-fluorobenzenesulfonyl chloride. NMRwas consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=517.

EXAMPLE 162N-2-(4-(4-(2-(3-trifluoromethylbenzene-sulfonylamino)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 19 mg (0.11 mmol) 3-trifluoromethyl-benzenesulfonylchloride. NMR was consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=567.

EXAMPLE 163N-2-(4-(4-(2-(4-fluorobenzenesulfonylamine)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 15 mg (0.11 mmol) 4-fluorobenzenesulfonyl chloride. NMRwas consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=517.

EXAMPLE 164N-2-(4-(4-(2-(2-thiophenesulfonylamino)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 14 mg (0.11 mmol) 2-thiophenesulfonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M−1=505.

EXAMPLE 165N-2-(4-(4-(2-(4-methoxybenzenesulfonylamine)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 16 mg (0.11 mmol) 4-methoxybenzenesulfonyl chloride. NMRwas consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=529.

EXAMPLE 166N-2-(4-(4-(2-(4-trifluoromethylbenzenesulfonylamine)ethyl)phenyl)phenyl)-propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 20 mg (0.11 mmol) 4-trifluoromethylbenzenesulfonylchloride. NMR was consistent with the proposed compound.

Electrospray Mass Spectrum: M−1=567.

EXAMPLE 167N-2-(4-(4-(2-(1-(5-dimethylamino)naphthalene-sulfonylamino)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.5 g (1.4 mmol) of material fromExample 50 and 22 mg (0.11 mmol) dansyl chloride. NMR was consistentwith the proposed compound.

Electrospray Mass Spectrum: M+1=594.

EXAMPLE 168 N-2-(4-(4-(2-(benzamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 15 mL (0.11 mmol) benzoyl chloride. NMR was consistentwith the proposed compound.

Electrospray Mass Spectrum: M+1=465.

EXAMPLE 169N-2-(4-(1-(2-(3-methylbutaneamido)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 13 mL (0.11 mmol) valeryl chloride. NMR was consistentwith the proposed compound.

Electrospray Mass Spectrum: M+1=445.

EXAMPLE 170 N-2-(4-(4-(2-(4-fluorobenzamido)ethyl)phenyl)-phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 13 mL (0.11 mmol) 4-fluorobenzoyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=483.

EXAMPLE 171 N-2-(4-(4-(2-(3-methoxybenzamido)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 18 mg (0.11 mmol) 3-methoxybenzoyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=495.

EXAMPLE 172 N-2-(4-(4-(2-(2-thiopheneamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 11 mL (0.11 mmol) 2-thiophenecarbonyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=471.

EXAMPLE 173 N-2-(4-(4-(2-(3-fluorobenzamido)ethyl)-phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 13 mL (0.11 mmol) 3-fluorobenzoyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=483.

EXAMPLE 174 N-2-(4-(4-(2-(4-methoxybenzamido)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 13 mL (0.11 mmol) 4-methoxybenzoyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=495.

EXAMPLE 175 N-2-(4-(4-(2-(2-methylpropaneamido)-ethyl)phenyl)phenylpropyl 2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 11 mL (0.11 mmol) isobutyryl chloride. NMR was consistentwith the proposed compound.

Electrospray Mass Spectrum: M+1=431.

EXAMPLE 176 N-2-(4-(4-(2-(2-methoxybenzamido)-ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 16 mL (0.11 mmol) 2-methoxybenzoyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=495.

EXAMPLE 177 N-2-(4-(4-(2-(phenylacetamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 14 mL (0.11 mmol) phenylacetyl chloride. NMR wasconsistent with the proposed compound.

Electrospray Mass Spectrum: M+1=479.

EXAMPLE 178 N-2-(4-(4-(2-(acetamido)ethyl)phenyl)phenyl)propyl2-propanesulfonamide

The title compound was prepared following the method of Example 147 andusing 1 mL of a stock solution of 0.6 g (1.8 mmol) of material fromExample 50 and 8 mL (0.11 mmol) acetyl chloride. NMR was consistent withthe proposed compound.

Electrospray Mass Spectrum: M−1=401.

EXAMPLE 179 N-2-(4-N-(benzamido)phenyl)propyl 2-propanesulfonamide

A solution of the material from Preparation 60 (333 mg, 0.93 mmol) indichloromethane (5 ml) was treated with benzoyl chloride (197 mg, 1.4mmol) and triethylamine (140 mg, 1.4 mmol). The reaction mixture wasstirred at room temperature for 3 h. Water (10 ml) was added to themixture and organic was extracted with ether (3×10 ml). The combinedorganic fraction was washed with brine (10 ml), dried over sodiumsulfate, and concentrated in vacuo to give the crude product which wasfurther purified by flash chromatography (SiO₂, 30% EtOAc: Hexanes). Thepure product was treated with trifluoroacetic acid: dichloromethane (5ml, 1:1 mixture). The mixture was stirred at room temperature for 1 h.Water (10 ml) was added to the mixture and the organic faction wasextracted with dichloromethane (3×10 ml). The combined organic fractionwas washed with water (2×10 ml), brine (10 ml), dried over sodiumsulfate, and concentrated in vacuo to give 248 mg (74%) of the titlecompound. NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺=360.

Analysis for C₁₉H₂₄N₂O₃S: Theory: C, 63.31; H, 6.71; N, 7.77. Found: C,63.17; H, 6.67; N, 7.73.

EXAMPLE 180 N-2-(4-N-(acetamido)phenyl)propyl 2-propanesulfonamide

The title compound 118 mg (75%) was prepared as a solid following themethod of Example 179, starting from the product of Preparation 60 andusing acetyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=360.

Analysis for C₁₄H₂₂N₂O₃S: Theory: C, 56.35; H, 7.43; N, 9.39. Found: C,57.36; H, 7.98; N, 10.40.

EXAMPLE 181 N-2-(4-N-(2-fluorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound 160 mg (75%) was prepared as a solid following themethod of Example 179, starting from the product of Preparation 60 andusing 2-fluorobenzoyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=378.3.

Analysis for C₁₉H₂₃FN₂O₃S: Theory: C, 60.30; H, 6.13; N, 7.40. Found: C,59.51; H, 5.98; N, 7.11.

EXAMPLE 182 N-2-(4-N-(2-furylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound 150 mg (47%) was prepared as a solid following themethod of Example 179, starting from the product of Preparation 60 andusing 2-furoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=352.3. Analysis forC₁₇H₂₂N₂O₄S: Theory: C, 58.29; H, 6.33; N, 7.99. Found: C, 58.19; H,6.81; N, 7.25.

EXAMPLE 183 N-2-(4-N-(2-thienylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound 150 mg (33%) was prepared as a solid following themethod of Example 1, starting from the product of Preparation 7 andusing 2-thiophene chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=366.2.

Analysis for C₁₇H₂₂N₂O₃S₂: Theory: C, 55.71; H, 6.05; N, 7.64. Found: C,55.59; H, 5.01; N, 7.80.

EXAMPLE 184 N-2-(4-N-(4-vinylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound 420 mg (56%) was prepared as a solid following themethod of Example 179, starting from the product of Preparation 60 andusing 4-vinylbenzoyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=387.2.

Analysis for C₂₁H₂₄N₂O₃S: Theory: C, 65.26; H, 6.78; N, 7.25. Found: C,64.99; H, 6.69; N, 7.17.

EXAMPLE 185 N-2-(4-N-(4-iodobenzamido)phenyl)propyl 2-propanesulfonamide

The title compound 610 mg (73%) was prepared as a solid following themethod of Example 179, starting from the product of Preparation 60 andusing 4-iodobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=487.2.

Analysis for C₁₉H₂₃N₂O₃S: Theory: C, 46.91; H, 4.73; N, 5.76. Found: C,47.13; H, 4.51; N, 5.60.

EXAMPLE 186 N-2-(4-(4-N-(1-(2-(2-propane)sulfonylamino)propylbenzamido)phenyl)propyl 2-propanesulfonamide

A 0° C. solution of the material from Preparation 67 (210 mg, 0.77 mmol)in dry acetone (5 ml) was treated with N-methyl morpholine (120 mg, 1.2mmol) and i-butyl chloroformate (120 mg, 0.85 mmol). The reactionmixture was stirred for 30 minutes. The solvent was removed and theresulting solid was dissolved in DMF (5 ml). The mixture was treatedwith aniline from Preparation 58 (220 mg, 0.85 mmol). The reactionmixture was stirred at room temperature for 16 h. Water (10 ml) wasadded to the mixture and organic was extracted with dichloromethane(3×10 ml). The combined organic fraction was washed with water (2×10ml), brine (10 ml), dried over sodium sulfate, and concentrated to givecrude product which was further purified by flash chromatography (SiO2,30% EtOAc: Hexane) to provide 100 mg (25%) of the pure product. NMR wasconsistent with the proposed title structure. Field Desorption MassSpectrum: M⁺=509.8.

Analysis for C₂₄H₃₅N₃O₅S₂: Theory: C, 56.78; H, 6.55; N, 8.28. Found: C,56.71; H, 6.64; N, 8.01.

EXAMPLE 187 N-2-(4-N-(cyclohexanecarboxamido)phenyl)propyl2-propanesulfonamide

A solution of the material of Preparation 58 (20 mg, 0.08 mmol) in dryTHF (1 ml) in a 4 ml teflon capped vial was treated withpoly(4-vinylpyridine) 2% crosslinked resin (200 mg, 1.6 mmol) andappropriate acid chloride (1.2 equivalent, 0.096 mmol). The vial wasshaken at room temperature for 24 h. The reaction was filtered thoughion exchange column (0.5 g pre packed SCX 1211-3039) to remove theunreacted aniline. Aminomethyl-polystyrene (400 mg, 0.8 mmol) was addedto the filtrate and the mixture was shaken at room temperature for 24 h.The reaction mixture was filtered through a cotton plug and the filtratewas concentrated to give pure amide. NMR of each amide was consistentwith the proposed structure. Field Desorption Mass Spectrum: M⁺=366.3.

EXAMPLE 188 N-2-(4-N-(4-fluorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-fluorobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=378.2.

EXAMPLE 189 N-2-(4-N-(3-methylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-methylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=374.2.

EXAMPLE 190 N-2-(4-N-(3-trifluoromethylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-methylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=428.2.

EXAMPLE 191 N-2-(4-N-(2-trifluoromethylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-trifluoromethylbenzoyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=428.2.

EXAMPLE 192 N-2-(4-N-(3-fluorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-fluorobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=378.2.

EXAMPLE 193 N-2-(4-N-(2-methoxybenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-methoxybenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=390.2

EXAMPLE 194 N-2-(4-N-(3-methoxybenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-methoxybenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=390.2.

EXAMPLE 195 N-2-(4-N-(4-t-butylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-t-butylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=416.2.

EXAMPLE 196 N-2-(4-N-(2,4-difluorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2,4-difluorobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=396.2.

EXAMPLE 197 N-2-(4-N-(4-methoxybenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-methoxybenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=390.2.

EXAMPLE 198 N-2-(4-N-(4-ethylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-ethylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=388.2.

EXAMPLE 199 N-2-(4-N-(cyclobutylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingcyclobutane carbonyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=338.2.

EXAMPLE 200 N-2-(4-N-(phenylacetamido)phenyl)propyl 2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingphenylacetyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=374.2

EXAMPLE 201 N-2-(4-N-(4-methylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-methylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=374.2.

EXAMPLE 202 N-2-(4-N-3-(5-methyl)isoxazolyl)carboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using5-methyl-3-isoxazole acid chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=365.2.

EXAMPLE 203N-2-(4-N-((2-fluoro4-trifluoromethyl)-benzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-fluoro-4-(trifluoromethyl)-benzoyl chloride. NMR was consistent withthe proposed title structure. Field Desorption Mass Spectrum: M⁺=446.1.

EXAMPLE 204 N-2-(4-N-(4-trifluoromethylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-(trifluoromethyl)benzoyl chloride. NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺=444.1.

EXAMPLE 205 N-2-(4-N-(4-n-butyloxybenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-n-butyloxybenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=432.2.

EXAMPLE 206 N-2-(4-N-(cyclopropylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingcyclopropane carbonyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=324.2.

EXAMPLE 207 N-2-(4-N-(cyclopentylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingcyclopentane carbonyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=353.

EXAMPLE 208 N-2-(4-N-(ethylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingpropionyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=312.

EXAMPLE 209 N-2-(4-N-(propylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingbutanoyl chloride. NMR was consistent with the proposed title structure.Field Desorption Mass Spectrum: M⁺=326.

EXAMPLE 210 N-2-(4-N-(5-isoxazolylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using5-isoxazole acid chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=351.

EXAMPLE 211 N-2-(4-N-(2-benzothiophenylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-benzothiophene acid chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=416.

EXAMPLE 212 N-2-(4-N-(4-phenylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-phenylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=436.

EXAMPLE 213 N-2-(4-N-(4-propylbenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-propylbenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=402.

EXAMPLE 214 N-2-(4-N-(4-cyanobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-cyanobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=385.

EXAMPLE 215 N-2-(4-N-(2-thiophenylacetamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-thiophene acetyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=380

EXAMPLE 216N-2-(4-N-4-(3-phenyl-5-methyl)isoxazolyl)-carboxamidophenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-phenyl-5-methyl-4-isoxazole acid chloride. NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺=441.

EXAMPLE 217 N-2-(4-N-(4-morpholinylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-morpholine carbonyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=369.

EXAMPLE 218 N-2-(4-N-(isonicotinylamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingisonicotinoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=361.

EXAMPLE 219 N-2-(4-N-(3-chlorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using3-chlorobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=395.

EXAMPLE 220 N-2-(4-N-(4-bromobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-bromobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=439.4.

EXAMPLE 221 N-2-(4-N-(4-chlorobenzamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using4-chlorobenzoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=395.

EXAMPLE 222 N-2-(4-N-(methyloxalylamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingmethyl oxalyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=343.

EXAMPLE 223 N-2-(4-N-(phenoxyacetamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingphenoxy acetyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=391.

EXAMPLE 224 N-2-(4-N-(acryloylamido)phenyl)propyl 2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingacryloyl chloride. NMR was consistent with the proposed title structure.Field Desorption Mass Spectrum: M⁺=311.

EXAMPLE 225 N-2-(4-N-(5-nitro-2-furylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using5-nitro-2-furoyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=396.

EXAMPLE 226 N-2-(4-N-(6-chloronicotinylcarbamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using6-chioronicotinyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=396.

EXAMPLE 227 N-2-(4-N-(piconioylcarbamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingpiconioyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=362.

EXAMPLE 228N-2-(4-N-(2-(S)-(−)-N-(trifluoroacetyl)pyrroidinylcarboxamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using(S)-(−)-N-(trifluoroacetyl)-prolyl chloride. NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺=450.

EXAMPLE 229 N-2-(4-N-(pivaloylcarbamido)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and usingpivaloyl chloride. NMR was consistent with the proposed title structure.Field Desorption Mass Spectrum: M⁺=341.

EXAMPLE 230 N-2-(4-N-(3-acetylphenylurea)phenyl)propyl2-propanesulfonamide

A solution of the material of Preparation 58 (15 mg, 0.058 mmol) in dryTHF (1 ml) in a 4 ml teflon capped vial was treated with3-acetylphenylisocynat (12 mg, 0.073 mmol). The reaction mixture wasshaken for 16 h. Aminomethylpolystyrene resin (150 mg, 0.3 mmol) wasadded to the reaction mixture and let this mixture stir for 2 h. Thereaction was filtered though ion exchange column (0.5 g pre packed SCX1211-3039) to remove the unreacted aniline. The reaction mixture wasfiltered through a cotton plug and the filtrate was concentrated to give32 mg of the pure amide. NMR of the product was consistent with theproposed structure. Field Desorption Mass Spectrum: M⁺=417.5.

EXAMPLE 231 N-2-(4-N-(2-(2-thienyl)ethylurea)phenyl)propyl2-propanesulfonamide

A solution of the material of Preparation 58 (15 mg, 0.058 mmol) in dryTHF (1 ml) in a 4 ml teflon capped vial was treated with2(thien-2-yl)ethylisocynate (12 mg, 0.073 mmol). The reaction mixturewas shaken for 16 h. Aminomethylpolystyrene resin (150 mg, 0.3 mmol) wasadded to the reaction mixture and let this mixture stir for 2 h. Thereaction was filtered though ion exchange column (0.5 g pre packed SCX1211-3039) to remove the unreacted aniline. The reaction mixture wasfiltered through a cotton plug and the filtrate was concentrated to give26.5 mg of the pure amide. NMR of the product was consistent with theproposed structure. Field Desorption Mass Spectrum: M⁺=409.6.

EXAMPLE 232 N-2-(4-(4-N-benzylpiperazino)phenyl)propyl2-propanesulfonamide

A solution of the material from Preparation 73 (80 mg, 0.18 mmol) in drytetrahydrofuran (10 ml) was treated with borane methylsulfide (1 M inTHF, 3 ml, 3 mmol). The reaction mixture was stirred while refluxing for4 h. The solution was cooled down to room temperature and was treatedwith 5N sodium hydroxide (5 ml) and methanol (5 ml). The mixture wasrefluxed for 12 h. The reaction mixture was cooled to room temperatureand water (10 ml) was added to the mixture. Organic was extracted withethyl acetate (3×10 ml). The combined organic fraction was washed withwater (2×10 ml), brine (10 ml), dried over potassium carbonate, andconcentrated in vacuo to give the crude material which was furtherpurified by flash chromatography (SiO₂, 30% dichloromethane: EtOAc) togive 34 mg (45%) of the pure product. NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺=436.

Analysis for C₂₃H₃₃N₃OS: Theory: C, 66.47; H, 8.00; N, 10.11. Found: C,65.72; H, 7.89; N, 9.68.

EXAMPLE 233 N-2-(4-(4-methylpiperazino)phenyl)propyl2-propanesulfonamide

A solution of the material from Preparation 72 (80 mg, 0.18 mmol) informic acid (0.7 ml) was treated with formaldehyde (0.7 ml, 37%). Thereaction mixture was heated at 80° C. for 1 h and then was cooled toroom temperature. Water (10 ml) was added to the mixture. The pH of themixture was brought to 10 by the addition of 1N sodium hydroxide.Organic was extracted with ethyl acetate (3×10 ml). The combined organicfraction was washed with water (2×10 ml), brine (10 ml), dried overpotassium carbonate, and concentrated in vacuo to 10 give the crudematerial which was further purified by flash chromatography (SiO₂, 10%methanol: dichloromethane) to give 46 mg (75%) of the pure product. NMRwas consistent with the proposed title structure. Field Desorption MassSpectrum: M⁺=436.

Analysis for C₁₇H₂₉N₃O₂S: Theory: C, 60.14; H, 8.61; N, 12.38. Found: C,59.31; H, 8.57; N, 11.58.

EXAMPLE 234 N-2-(4-(2-thienyl)methylaminophenyl)propyl2-propanesulfonamide

A solution of the product from Preparation 58 (0.15 g, 0.42 mmol) inmethanol (3 ml) and glacial acetic acid (1 drop) was treated with2-thiophenecarboxaldehyde (0.031 g, 0.28 mmol). The reaction was stirredat ambient for 90 minutes and sodium borohydride (0.015 g, 0.42 mmol)added. The reaction was stirred for 16 h. Water (5 ml) was added and theorganic extracted with methylene chloride (2×10 ml). The combinedorganic layers were washed with brine, dried over magnesium sulfate andconcentrated. The crude product was dissolved in methylene chloride (3ml) and TFA (5 drops) added. The reaction was stirred for 3 h atambient, then water added (3 ml). The organic was extracted withmethylene chloride (2×10 ml). The combined organic layers were washedwith brine, dried over magnesium sulfate and concentrated. The crudetitle product was purified by flash chromatography (SiO₂, 30% EtOAc:hexanes) to give 0.060 g (60%) of the pure product. NMR was consistentwith the proposed title structure. Field Desorption Mass Spectrum:M⁺=353.

Analysis for C₁₇H₂₄N₂O₂S₂: Theory: C, 57.92; H, 6.86; N, 7.95. Found: C,58.11; H, 6.71; N, 7.79.

EXAMPLE 235 N-2-(4-(2-furyl)methylaminophenyl)propyl2-propanesulfonamide

The title compound 80 mg (85%) was prepared as an oil following themethod of Example 234, starting from the material of Preparation 58 andusing 2-furaldehyde. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=336.

Analysis for C₁₇H₂₄N₂O₃S: Theory: C, 60.69; H, 7.19; N, 8.33. Found: C,60.52; H, 7.03; N, 8.45.

EXAMPLE 236 N-2-(4-(3-thienyl)methylaminophenyl)propyl2-propanesulfonamide

The title compound 70 mg (54%) was prepared as an oil following themethod of Example 234, starting from the product of Preparation 58 andusing 3-thiophene-carboxaldehyde. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=336.1.

Analysis for C₁₇H₂₄N₂O₃S: Theory: C, 60.69; H, 7.19; N, 8.33. Found: C,60.89; H, 7.16; N, 8.09.

EXAMPLE 237 N-2-(4-(3-furyl)methylaminophenyl)propyl2-propanesulfonamide

The title compound 40 mg (21%) was prepared as an oil following themethod of Example 234, starting from the product of Preparation 58 andusing 3-furaldehyde. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=352.

Analysis for C₁₇H₂₄N₂O₂S₂: Theory: C, 57.92; H, 6.86; N, 7.95. Found: C,57.80; H, 6.63; N, 7.78.

EXAMPLE 238 N-2-(4-(2-fluorophenyl)methylamino)phenyl)propyl2-propanesulfonamide

The title compound 52 mg (52%) was prepared as an oil following themethod of Example 234, starting from the product of Preparation 58 andusing 2-fluoro-benzaldehyde. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=xxx.

Analysis for C₁₉H₂₅FN₂O₂S:

EXAMPLE 239 N-2-(4-morpholinophenyl)propyl 2-propanesulfonamide

The title compound 70 mg (47%) was prepared as an oil following themethod of Preparation 65, starting from the product of Preparation 39(part 1) and using morpholine. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum M⁺=xxx

Analysis for C₁₆H₂₆N₂O₃S:

EXAMPLE 240 N-2-(4-(2-fluorophenyl)methoxyphenyl)propyl2-propanesulfonamide

A solution of the product of Preparation 36 (0.3 g, 0.84 mmol)in dry DMF(20 ml) was treated with sodium hydride (0.037 g, 0.92 mmol) and2-fluorobenzyl bromide (0.17 g, 0.92 mmol. The reaction mixture wasstirred at ambient for 5 h. Water (10 ml) was added and the organicextracted with ether(2×30 ml). The combined organic layers were washedwith brine (20 ml), dried over magnesium sulfate, and concentrated invacuo. The crude material was taken up in methylene chloride (20 ml) andTFA (2 ml) added. The reaction mixture was stirred at ambient for 3 h.Water (5 ml) was added and the organic extracted with methylene chloride(2×20 ml). The combined organic layers were washed with brine (20 ml),dried over magnesium sulfate, and concentrated in vacuo. The crudeproduct was further purified by flash chromatography (SiO2, 30% EtOAc:hexanes) to give 0.25 g (82%) of a white solid as a pure product. NMRwas consistent with the proposed title structure. Field Desorption MassSpectrum: M+=365.

Analysis for C₁₉H₂₄FNO₃S: Theory: C, 62.44; H, 6.62; N, 3.83. Found: C,62.42; H, 6.59; N, 3.76.

EXAMPLE 241 N-2-(4-(2-tetrahydrofuryl)methoxyphenyl)propyl2-propanesulfonamide

The title compound 150 mg (52%) was prepared as a solid following themethod of Example 240, starting from the product of Preparation 36 andusing tetrahydro-furfuryl bromide. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M+=341.1.

Analysis for C₁₇H₂₇NO₄S: Theory: C, 59.80; H, 7.97; N, 4.10. Found: C,59.84; H, 8.00; N, 3.80.

EXAMPLE 242 N-2-(4-benzoylmethylphenyl)propyl 2-propanesulfonamide

A solution of the product of Preparation 39 (1.0 g, 3.2 mmol) in dry,degassed tetrahydrofuran (25 ml) was treated with palladium chloride(0.028 g, 0.16 mmol), tri-o-tolylphosphine (0.097 g, 0.32 mmol),tributyl-influoride (1.0 g, 3.4 mmol), and1-phenyl-1-(trimethylsiloxy)ethylene (1.0 ml, 4.8 mmol). The reactionmixture was heated to reflux for 16 h. Water (50 ml) was added to themixture and the organic layer was extracted with ether (3×50 ml). Thecombined organic layers were washed with brine (50 ml), dried overmagnesium sulfate, and concentrated in vacuo to give the crude productwhich was further purified by flash chromatography (SiO₂, 30% EtOAc:Hexanes) to give 0.28 g (24%) of an orange solid as a pure product. NMRwas consistent with the proposed title structure. Ion Spray MassSpectrum: M+=1=360.0, M−1=358.0.

Analysis for C₂₀H₂₅NO₃S: Theory: C, 66.82; H, 7.01; N, 3.90. Found: C,66.86; H, 7.16; N, 3.85.

EXAMPLE 243 N-2-(4-acetylphenyl)propyl 2-propanesulfonamide

A −80° C. solution of the product of Preparation 39 (2.0 g, 6.4 mmol) indry THF (30 ml) was slowly treated with a solution of nBuLi (8.0 ml,13.5 mmol, 1.7M solution in hexanes). The reaction was stirred at −80C.for 30 min and then treated with dimethylacetamide (0.6 ml, 12.8 mmol).The reaction was treated with an aqueous, saturated solution of ammoniumchloride at −80° C. (2 ml). Water (30 ml) was added to the mixture andthe organic layer extracted with ether (2×50 ml). The combined organiclayers were washed with brine (50 ml), dried over magnesium sulfate andconcentrated. The crude product was further purified by flashchromatography (SiO₂, 30% EtOAc: hexanes) to give 1.0 g (55%) of a whitesolid as the pure product. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=283.0.

Analysis for C₁₄H₂₁NO₃S: Theory: C, 59.34; H, 7.47; N, 4.94. Found: C,59.36; H, 7.65; N, 5.10.

EXAMPLE 244 N-2-(4-cyclopropylcarbanoylphenyl)propyl2-propanesulfonamide

A 0° C. solution of the product of Preparation 67 (0.18 g, 0.63 mmol) inacetone was treated with 4-methyl morpholine (0.095 g, 0.94 mmol), andisobutyl chloroformate (0.094 g, 0.69 mmol). The reaction mixture wasstirred for 30 min and concentrated in vacuo. The resulting white solidwas taken up in DMF and cyclopropylamine (0.040 g, 0.69 mmol), and DMAP(catalytic) added. The reaction mixture was stirred for 16 h at ambienttemperature. Water (5 ml) was added and the organic extracted withmethylene chloride (2×20 ml). The combined organic layers were washedwith an aqueous saturated solution of NaHSO₄(20 ml), brine (20 ml),dried over magnesium sulfate and concentrated in vacuo. The crudematerial was purified by flash chromatography (SiO₂, 30% EtOAc: hexanes)to give 0.09 g (56%) of a white solid as a pure product. NMR wasconsistent with the proposed title structure. Field Desorption MassSpectrum: M⁺=324.2.

Analysis for C₁₆H₂₄N₂O₃S: Theory: C, 59.23; H, 7.46; N, 8.63. Found: C,59.35; H, 7.69; N, 8.53.

EXAMPLE 245 N-2-(4-cyclopentylcarbanoylphenyl)propyl2-propanesulfonamide

The title compound 90 mg (41%) was prepared as a solid following themethod of Example 244, starting from the material of Preparation 67 andusing cyclopentyl-amine. NMR was consistent with the proposed titlestructure. Filed Desorption Mass Spectrum: M⁺=352.2.

Analysis for C₁₈H₂₈N₂O₃S: Theory: C, 61.33; H, 8.01; N, 7.95. Found: C,61.08; H, 7.78; N, 8.07.

EXAMPLE 246 N-2-(4-(2-fluorophenyl)carbanoylphenyl)propyl2-propanesulfonamide

The title compound 105 mg (50%) was prepared as a solid following themethod of Example 244, starting from the material of Preparation 67 andusing 2-fluoroaniline. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=378.

Analysis for C₁₈H₂₈N₂O₃S: Theory: C, 61.20; H, 6.42; N, 7.14. Found: C,61.12; H, 6.27; N, 6.87.

EXAMPLE 247 N-2-(4-benzylsulfonylaminophenyl)propyl 2-propanesulfonamide

The title compound 63 mg (82%) was prepared as a solid following themethod of Example 179, starting from the material of Preparation 58 andusing benzylsulfonyl chloride. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=396.

EXAMPLE 248 N-2-(4-(2-thienyl)sulfonylamino)phenyl)propyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 187, starting from the product of Preparation 58 and using2-thienylsulfonyl chloride. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=428.2.

EXAMPLES 249 AND 250 N-2-(4-(3-oxocyclopentyl)phenyl)propyl2-propanesulfonamide (A) and N-2-(4-(3-hydroxycyclopentyl)phenyl)propyl2-propanesulfonamide (B)

A solution of the material from Preparation 75 (0.15 g, 0.47 mmol) inEtOAc (5 ml) was treated with palladium on carbon (0.02 g, 10 mole %)under a hydrogen atmosphere. The mixture was stirred at ambient for 4 hand then heated to 50° C. for 2 h. The reaction was filtered through acelite cake and the filtrate concentrated in vacuo. The crude mixture ofboth title products was purified by flash chromatography (SiO₂, 70%EtOAc: hexanes) to give 0.06 g (40%) of the first title compound (A) and0.05 g (33%) of the second title (B).

(A) NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺=323.

Analysis for C₁₇H₂₅NO₃S: Theory: C, 63.13; H, 7.91; N, 4.33. Found: C,63.34; H, 7.76; N, 4.30.

(B) NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺=325.

Analysis for C₁₇H₂₇NO₃S: Theory: C, 62.74; H, 8.36; N, 4.30. Found: C,62.54; H, 8.27; N, 4.24.

EXAMPLE 251 N-2-(4-(2-hydroxy-2-phenyl(ethylphenyl)propyl2-propanesulfonamide

A solution of the title compound from Example 242 (65 mg, 0.18 mmol) inethanol (5 ml) was treated with sodium borohydride (9 mg, 0.22 mmol).The reaction mixture was stirred for 2 h and water (2 ml) added slowly.The mixture was extracted with methylene chloride (2×10 ml). Thecombined organic layers were washed with brine 95 ml), dried overmagnesium sulfate and concentrated in vacuo. The resulting crude productwas diluted with EtOAc and filtered through a 1 inch silica gel plus andconcentrated in vacuo to give 61 mg (94%) of a colorless oil as a pureproduct. NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum M⁺=361.

Analysis for C₂₀H₂₇NO₃S: Theory: C, 66.45; H, 7.53; N, 3.87. Found: C,66.36; H, 7.77; N, 3.63.

EXAMPLE 252 N-2-(4-formylphenyl)propyl 2-propanesulfonamide

The title compound 1.18 g (68%) was prepared as a solid following themethod of Example 243, starting from the product of Preparation 39 andusing dimethyl-formamide. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=269.3.

Analysis for C₁₃H₁₉NO₃S: Theory: C, 57.97; H, 7.11; N, 5.20. Found: C,57.78; H, 6.95; N, 5.00.

EXAMPLE 253 N-2-(4-(1-pyrrolidinyl)phenyl)propyl 2-propanesulfonamide

A solution of material from Preparation 60 (0.17 g, 0.45 mmol) in DMF(20 ml) was treated with diiodobutane (0.15 g, 0.95 mmol) followed bysodium hydride (38 mg, 0.47 mmol). The reaction mixture was heated to70° C. for 4 h. Water (10 ml) was added and the organic extracted withether (2×20 ml). The combined organic layers were washed with brine (10ml), dried over magnesium sulfate and concentrated. The crude productwas further purified by flash chromatography (SiO₂, 20% EtOAc: hexanes)to give 0.10 g of an oil. This oil was diluted with methylene chloride(10 ml) and TFA (2 ml) added. The reaction was stirred at ambient for 3h. Water (5 ml) was added and the organic further washed with brine (5ml), dried over magnesium sulfate and concentrated in vacuo. Flashchromatography (SiO2, 30% EtOAc: hexanes) gave 20 mg (14%) of a whitesolid as the pure product. NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺=310.2.

EXAMPLE 254 N-2-(4-N-(benzamido)phenyl)-2-methylpropyl2-propanesulfonamide

To a solution of the amine from Preparation 82 (150 mg, 0.56 mmol) andtriethylamine (65 mg, 1.1 eq) in dichloromethane (20 ml) was addeddropwise benzoyl chloride (87 mg., 1.1 Eq)in dichloromethane (5 ml) atroom temperature under nitrogen. After 1 hour, the reaction wascomplete. The solution was washed once with H₂O, dried over K₂CO₃, andconcentrated under reduced pressure to yield 206 mg. of a solid.Material was recrystallized from hexane/ethyl acetate 5:1 to yield 141mg. as crystals. m.p. 202.5°-204° C. (67%). NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺375

Analysis for C₂₀H₂₆N₂O₃S: Theory: C, 64.14; H, 7.00; N, 7.48. Found: C,64.20; H, 7.25; N, 7.58.

EXAMPLE 255 N-2-(4-N-(cyclobutylcarboxamido)phenyl)-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting from the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated withcyclobutanecarbonyl chloride (48 mg., 1.1 Eq). The resulting solid wasrecrystallized from ethyl acetate/hexane 4:1 to yield 74 mg. ofcrystals. m.p. 186°-188° C. (57%). NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺353 Analysis forC₁₈H₂₈N₂O₃S: Theory: C, 61.33; H, 8.01; N, 7.95. Found: C, 61.51; H,7.77; N, 7.80.

EXAMPLE 256 N-2-(4-N-(propanoylamido)phenyl)-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting from the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with propanoylchloride (40 mg., 1.1 Eq.). The resulting solid was recrystallized fromethyl acetate/hexane 4:1 to yield 75 mg. of crystals. m.p. 154°-155° C.(58%). NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺327 Analysis for C₁₆H₂₆N₂O₃S: Theory: C,58.87; H, 8.03; N, 8.58. Found: C, 58.96; H, 7.75; N, 8.54.

EXAMPLE 257 N-2-(4-N-(2-thienylcarboxamido)phenyl)-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting from the product of Preparation 82 (100 mg, 0.37mmol) and treating with 2-thiophene chloride (66 mg., 1.2 Eq.). Theresulting solid was recrystallized from ethyl acetate/hexane 2:1 toyield 77 mg. of crystals. m.p. 183°-185° C. (55%). NMR was consistentwith the proposed title structure. Field Desorption Mass Spectrum: M⁺381Analysis for C₁₈H₂₄N₂O₃S₂: Theory: C, 56.81; H, 6.36; N, 7.36. Found: C,56.90; H, 6.57; N, 7.39.

EXAMPLE 258N-2-(4-N-(3-(5-methyl)isoxazolylcarboxamido)phenyl)-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting from the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with5-methyl-3-isoxazole acid chloride (68 mg., 1.2 Eq.). The resultingsolid was recrystallized from hexane/ethyl acetate 1:1 to yield 83 mg.of crystals. m.p. 118°-120° C. (59%) NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺380 Analysisfor C₁₈H₂₅N₃O₄S Theory: C, 56.97; H, 6.64; N, 11.07. Found: C, 57.11; H,6.68; N, 11.16.

EXAMPLE 259 N-2-(4-N-(phenoxymethylcarboxamido)phenyl)-2-methylprolyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting with the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with phenoxyacetylchloride (76 mg., 1.2 Eq.). The resulting solid was recrystallized fromhexane/ethyl acetate 1:1 to yield 80 mg. of crystals. m.p. 143°-144° C.(54%). NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺405

Analysis for C₂₁H₂₈N₂O₄S: Theory: C, 62.35; H, 6.98; N, 6.93. Found: C,62.37; H, 6.83; N, 6.74.

EXAMPLE 260 N-2-(4-N-(4-ethylbenzamido)phenyl)-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting with the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with4-ethylbenzoyl chloride (76 mg., 1.2 Eq.). The resulting solid wasrecrystallized from hexane/ethyl acetate 1:1 to yield 68 mg. ofcrystals. m.p. 118°-119° C. (46%). NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺403 Analysis forC₂₂H₃₀N₂O₃S: Theory: C, 65.64; H, 7.51; N, 6.96. Found: C, 65.84; H,7.47; N, 7.06.

EXAMPLE 261 N-2-[4-N-(cyclohexylcarboxamido)phenyl]-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting with the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (45 mg., 1.2 Eq.) was treated withcyclohexanecarbonyl chloride (51 mg., 1.2 Eq.). The resulting solid wasrecrystallized from hexane/ethyl acetate 3:1 to yield 91 mg. ofcrystals. m.p. 203°-205° C. (65%). NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺381 Analysis forC₂₀H₃₂N₂O₃S: Theory: C, 63.13; H, 8.48; N, 7.36. Found: C, 63.41; H,8.66; N, 7.58.

EXAMPLE 262 N-2-[4-N-(isonicotinylamido)phenyl]-2-methylpropyl2-propanesulfonamide

The title compound was prepared as a solid following the method ofExample 254, starting with the product of Preparation 82 (100 mg, 0.37mmol) and triethylamine (90 mg., 2.2 Eq.) was treated with isonicotinoylchloride HCl (100 mg., 1.2 Eq.). The resulting solid was recrystallizedfrom hexane/ethyl acetate 1:1 to yield 90 mg. as crystals. m.p.174°-175° C. (65%). NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺376 Analysis forC₁₉H₂₅N₃O₃S: Theory: C, 60.78; H, 6.71; N, 11.19. Found: C, 61.01; H,7.01; N, 11.04.

EXAMPLE 263 N-2-(4-N-(benzamido)phenyl)propyl 2-dimethylsulfamide

To a solution of the amine from Preparation 84 (100 mg, 0.39 mmol) andtriethylamine (45 mg, 0.43 mmol) in dichloromethane (20 ml) was addeddropwise benzoyl chloride (61 mg., 1.2 Eq.) in dichloromethane (5 ml) atroom temperature under nitrogen. After 1 hour, reaction was complete.The solution was washed once with H₂O, dried over K₂CO₃, andconcentrated under reduced pressure to yield 139 mg. of a solid.Material was recrystallized from hexane/ethyl acetate 3:1 to yield 70mg. as crystals. m.p. 146°-148° C. (50%). NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺362

Analysis for C₁₈H₂₃N₃O₃S: Theory: C, 59.81; H, 6.41; N, 11.63. Found: C,60.08; H, 6.36; N, 11.45.

EXAMPLE 264 N-2-(4-N-(cyclobutylcarboxamido)phenyl)propyl N,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting from the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated withcyclobutanecarbonyl chloride (55 mg., 1.2 Eq.). The resulting solid wasrecrystallized from ethyl acetate/hexane 3:1 to yield 55 mg. ofcrystals. m.p. 161°-162° C. (42%). NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺340 Analysis forC₁₆H₂₅N₃O₃S Theory: C, 56.61; H, 7.42; N, 12.38. Found: C, 56.91; H,7.66; N, 12.45.

EXAMPLE 265 N-2-(4-N-(propionylamido)phenyl)propyl N,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting from the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with propionylchloride (40 mg., 1.2 Eq.). The resulting solid was recrystallized fromethyl acetate/hexane 4:1 to yield 57 mg. of crystals. m.p. 109°-110.5°C. (51%). NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺314 Analysis for C₁₄H₂₃N₃O₃S: Theory: C,53.65; H, 7.40; N, 13.41. Found: C, 53.91; H, 7.48; N, 13.41.

EXAMPLE 266 N-2-(4-N-(2-thienylcarboxamido)phenyl)propylN,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting from the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with 2-thiophenechloride (70 mg., 1.2 Eq.). The resulting solid was recrystallized fromethyl acetate/hexane 1:1 to yield 62 mg. of crystals. m.p. 148°-150° C.(43%). NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺368 Analysis for C₁₆H₂₁N₃O₃S₂: Theory: C,52.30; H, 5.76; N, 11.43. Found: C, 52.59; H, 5.78; N, 11.23.

EXAMPLE 267 N-2-(4-N-(3-(5-methyl)isoxazolylcarboxamido)phenyl)propylN,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting from the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with5-methyl-3-isoxazole acid chloride (70 mg., 1.2 Eq.). The resultingsolid was recrystallized from hexane/ethyl acetate 4:1 to yield 78 mg.of crystals. m.p. 138.5°-140° C. (55%) NMR was consistent with theproposed title structure. Field Desorption Mass Spectrum: M⁺367 Analysisfor C₁₆H₂₂N₄O₄S: Theory: C, 52.44; H, 6.05; N, 15.29. Found: C, 52.71;H, 6.20; N, 15.28.

EXAMPLE 268 N-2-(4-N-(phenoxymethylcarboxamido)phenyl)propyl NN-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting with the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with phenoxyacetylchloride (73 mg., 1.2 Eq.). The resulting solid was recrystallized fromhexane/ethyl acetate 9:1 to yield 73 mg. of crystals. m.p. 120°-121° C.(48%). NMR was consistent with the proposed title structure. FieldDesorption Mass Spectrum: M⁺392 Analysis for C₁₉H₂₅N₃O₄S: Theory: C,58.29; H, 6.44; N, 10.73. Found: C, 58.49; H, 6.22; N, 10.45.

EXAMPLE 269 N-2-(4-N-(4-ethylbenzamido)phenyl)propyl N,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting with the product of Preparation 84 (100 mg, 0.39mmol) and triethylamine (45 mg., 1.2 Eq.) was treated with4-ethylbenzoyl chloride (80 mg., 1.2 Eq.). The resulting solid wasrecrystallized from hexane/ethyl acetate 2:1 to yield 87 mg. ofcrystals. m.p. 131°-133° C. (57%). NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺390 Analysis forC₂₀H₂₇N₃O₃S: Theory: C, 61.67; H, 6.99; N, 10.79. Found: C, 61.49; H,6.79; N, 10.97.

EXAMPLE 270 N-2-(4-N-(isonicotinylamido)phenyl)propylN,N-dimethylsulfamide

The title compound was prepared as a solid following the method ofExample 263, starting with the product of Preparation 84 (73 mg, 0.29mmol) and triethylamine (75 mg., 2.2 Eq.) was treated with isonicotinoylchloride HCl (78 mg., 1.2 Eq.). The resulting solid was recrystallizedfrom hexane/ethyl acetate 2:1 to yield 70 mg. as crystals. m.p.156°-157° C. (50%). NMR was consistent with the proposed titlestructure. Field Desorption Mass Spectrum: M⁺363 Analysis forC₁₇H₂₂N₄O₃S Theory: C, 56.34; H, 6.12; N, 15.46. Found: C, 56.62; H,5.80; N, 15.17.

EXAMPLE 271 N-2-(2-thien-3-yl-5-thienyl)propyl 2-propanesulfonamide

A. (2-Acetyl-5-thien-3-yl)thiophene: A solution of 1.45 g (7.10 mmol) of2-acetyl-5-bromothiophene, 2.0 g (7.81 mmol) of thiophene 3-boronicacid, 328 mg (0.28 mmol) of tetrakis(triphenylphosphine)palladium and1.47 g (10.6 mmol) of potassium carbonate in 32 ml of dioxane and 8 mlof water, was heated at 90° C. for 3 days. Brine was added and extractedthree times with ethyl acetate. The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. Chromatography (300 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 1.10 g (74%) of thetitle compound.

B. 2-[2-(thien-3-yl)-5-thienyl]propylamine: To a −15° C. solution of 1.1g (5.3 mmol) of the material prepared in step A and 1.05 g (5.35 mmol)of tosylmethyl isocyanide in 18 ml of DME, a hot solution of 1.07 g(9.54 mmol) of potassium tert-butoxide in 5 ml of tert-butanol was addedslowly. The mixture was stirred at −5° C. for 45 min and 2 h at ambienttemperature. Water was added and extracted three times with diethylether. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was dissolved in 15 ml ofdiethyl ether and then was added to a suspension of 218 mg (5.75) oflithium aluminum hydride in 5 ml of diethyl ether. The mixture wasstirred at ambient temperature for 2 h. Na₂SO₄.10H₂O was added, and themixture stirred for 30 min at ambient temperature. The solid wasfiltered and the organic solution was concentrated in vacuo.Chromatography (150 g of silica gel, ethyl acetate/hexane/methanol10/10/1) of the residue afforded 250 mg (22%) of the title compound.

C. To a 0° C. solution of 200 mg (0.89 mmol) of the material prepared instep B in dichloromethane (5 ml), triethylamine 0.15 ml (1.07 mmol) wasadded, followed by isopropylsulfonyl chloride (0.12 ml, 1.07 mmol). Theice-bath was removed and the solution was stirred at ambient temperaturefor overnight. The organic solution was washed with 1N hydrochloricacid, sodium bicarbonate saturated solution, brine, dried over Na₂SO₄filtered and concentrated in vacuo. Chromatography (100 g of silica gel,25% ethyl acetate/hexane) of the residue afforded 61 mg (21%) of thetitle compound. Analysis calculated for C₁₄H₁₉NO₂S₃: %C, 51.03; %H,5.81; %N, 4.25. Found: %C, 51.30; %H, 5.81; %N, 4.25. Field DesorptionMass Spectrum: M=329.

EXAMPLE 272 N-2-(2-thien-3-yl-4-thienyl)propyl 2-propanesulfonamide

Prepared as in Example 271 using 4.38 g (21.31 mmol) of4-acetyl-2-bromothiophene and 3 g (23.44 mmol) of thiophene 3-boronicacid. After three steps, afforded 421 mg (6% overall yield. FieldDesorption Mass Spectrum: M=329.

EXAMPLE 273 N-2-(2-thien-3-yl-5-pyridyl)propyl 2-propanesulfonamide

A. 2-(2-thien-3-yl-5-pyridyl)propanenitrile: A solution of 960 mg (4.8mmol) of 5-acetyl-2-bromopyridine, 676 mg (5.28 mmol) of thiophene3-boronic acid, 222 mg (0.19 mmol) of tetrakis(triphenylphosphine)palladium and 995 mg (7.2 mmol) of potassium carbonate in 13 ml ofdioxane and 3 ml of water, was heated at 90° C. overnight. Brine wasadded and extracted three times with ethyl acetate. The organic phasewas dried over Na₂SO₄, filtered and concentrated in vacuo. To a solutionof the crude and 475 mg (14.4 mmol) of lithium cyanide in 16 ml of THF,2.2 ml (14.4 mmol) of diethylcyanophosphonate was added neat at ambienttemperature. The mixture was stirred at ambient temperature for 30 min.Water was added and extracted with a 1:1 solution of ethylacetate/hexane. The organic solution was dried over Na₂SO₄ filtered andconcentrated in vacuo. The crude was dissolved in 10 ml of THF and addeddropwise to a solution of samarium iodide, prepared from 3.32, g (22.08mmol) of samarium and 3.89 g (13.8 mmol) of 1,2-diiodoethane. Themixture was stirred for 1 h. A 2.5 N solution of hydrochloric acid wasadded and extracted three times with diethyl ether. The organic phasewas washed with a 1 N solution of sodium thiosulfate. The organicsolution was dried over Na₂SO₄ filtered and concentrated in vacuo.Chromatography (100 g of silica gel, 25% ethyl acetate/hexane) of theresidue afforded 225 mg (22%) of the title compound.

B. To an ambient temperature solution of 214 mg (1 mmol) of materialprepared in step A in 5 ml of THF was added dropwise 0.11 ml of a 10 Msolution borane-methyl sulfide complex (1.1 mmol) in THF. The mixturewas stirred at ambient temperature for 2 h. Then, 0.1 ml of a 10 Msolution borane-methyl sulfide complex (1.0 mmol) in THF were added andthe mixture stirred overnight. A saturated solution of hydrochloric acidin methanol (5 ml) was added, and stirred for 10 min. The solution wasconcentrated in vacuo. The crude was dissolved in dichloromethane (5 ml)and cooled to 0° C., triethylamine 0.44 ml (3.2 mmol) was added,followed by isopropylsulfonyl chloride (0.14 ml, 1.2 mmol). The ice-bathwas removed and the solution was stirred at ambient temperature for 2 h.The organic solution was washed with 1N hydrochloric acid, sodiumbicarbonate saturated solution, brine, dried over Na₂SO₄ filtered andconcentrated in vacuo. Chromatography (50 g of silica gel, 33% ethylacetate/hexane) of the residue afforded 25 mg (7%) of the titlecompound. Field Desorption Mass Spectrum: M=324.

EXAMPLE 274 (+)-N-2R-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide

To a solution of 0.75 g (3.5 mmol) of material from Preparation 102 and0.60 mL (3.8 mmol) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in 10 mL ofdichloromethane at 0° C. was added 0.40 mL (3.5 mmol) of2-propanesulfonyl chloride. The mixture was stirred at room temperaturefor 4 hr and then was washed with 10 mL of 1N hydrochloric acid, theorganic layer was separated and the aqueous layer extracted one timewith 5 mL of dichloromethane. The combined organics were dried (MgSO₄),filtered and concentrated in vacuo. Recrystallizaton from methyl alcoholafforded 0.46 g (41%) of the title compound.

Analysis calculated for C₁₆H₂₁NO₂S₂: %C, 59.41; %H, 6.54; %N, 4.33.Found: %C, 59.69; %H, 6.68; %N, 4.42.

Field Desorption Mass Spectrum: M+1=324.

[α]_(D) ²⁰=+42.55 (c=0.99, CHCl₃).

EXAMPLE 275 (+)-N-2S-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide

Following the procedure of Example 274 and using material fromPreparation 103 instead of material form Preparation 102 afforded 0.45 g(39%) of the title compound.

Analysis calculated for C₁₆H₂₁NO₂S₂: %C, 59.41; %H, 6.54; %N, 4.33.Found: %C, 59.71; %H, 6.35; %N, 4.43.

Field Desorption Mass Spectrum: M+1=324.

[α]_(D) ²⁰=−43.98 (c=1.05, CHCl₃).

EXAMPLE 276 (+)-N-2R-(4-(3-thienyl)phenyl)propyl N′,N′-dimethylsulfamide

To a solution of 0.1 g (0.46 mmol) of material from Preparation 102 and0.07 mL (0.46 mmol) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in 10 mL ofdichloromethane at 0° C. was added 0.05 mL (0.46 mmol) ofN,N-dimethyl-sulfamoyl chloride. The mixture was stirred at roomtemperature for 4 hr and then was washed with 10 mL of 1N hydrochloricacid, the organic layer was separated and the aqueous layer extractedone time with 5 mL of dichloromethane. The combined organics were dried(MgSO₄), filtered and concentrated in vacuo. Chromatography (10 g ofsilica gel, 25% ethyl acetate/-hexane) of the residue afforded 0.04 g(26%) of the title compound.

Analysis calculated for C₁₅H₂₀N₂O₂S₂: %C, 55.53; %H, 6.21; %N, 8.63.Found: %C, 55.39; %H, 6.08; %N, 8.50.

Field Desorption Mass Spectrum: M+1=325.

[α]_(D) ²⁰=+20.75 (c=0.77, CHCl₃).

EXAMPLE 277 (−)-N-2S-(4-(3-thienyl)phenyl)propyl N′,N′-dimethylsulfamide

Following the procedure of Example 276 and using material fromPreparation 103 instead of material form Preparation 102 afforded 0.02 g(13%) of the title compound.

Analysis calculated for C₁₅H₂₀N₂O₂S₂: %C, 55.53; %H, 6.21; %N, 8.63.Found: %C, 55.31; %H, 6.23; %N, 8.36.

Field Desorption Mass Spectrum: M+1=325.

[α]_(D) ²⁰=−25.81 (c=1.24, CHCl₃).

EXAMPLE 278 (+-N-2R-(4-(2-pyridyl)phenyl)propyl 2-propanesulfonamide

A. (R)-2-(4-(2-pyridyl)phenyl)-N-(t-butoxy-carbonyl)propyl amine: To asolution of 1.0 g (3.2 mmol) of material from Preparation 92 and 1.2 g(3.2 mmol) of 2-(tri-n-butylstannyl)pyridine in 10 mL of dioxane wasadded 0.18 g (0.16 mmol) of tetrakis (triphenyl-phosphine)palladium(0).The mixture was heated at 100° C. for 18 h. The mixture was cooled andconcentrated in vacuo. Chromatography (150 g of silica gel, 25% ethylacetate/hexane) of the residue afforded 0.87 g (85%) of the titlecompound.

B. To a solution of 0.85 g (2.7 mmol) of material from Example 278A in 5mL of ethyl acetate was added 5 mL of hydrochloric acid saturated ethylacetate. The mixture was stirred at room temperature for 3 hr and thenconcentrated in vacuo. The residue was suspended in 5 mL of methylalcohol and concentrated in vacuo and then dissolved in 5 mL ofdichloromethane. To the mixture was added 1.2 mL (8.4 mmol) of1,8-diazabicyclo[5.4.0]undec-7-ene and the solution was cooled to 0° C.To this mixture was added 0.30 mL (2.7 mmol) of 2-propanesulfonylchloride. The mixture was stirred at room temperature for 4 hr and thenwas washed with 5 mL of 1N hydrochloric acid, the organic layer wasseparated and the aqueous layer extracted Three times with 5 mL ofdichloromethane. The combined organics were dried (MgSO₄), filtered andconcentrated in vacuo. Chromatography (25 g of silica gel, 50% ethylacetate/hexane) of the residue afforded 0.49 g (57%) of the titlecompound.

Analysis calculated for C₁₇H₂₂N₂O₂S: %C, 64.12; %H, 6.96; %N, 8.80.Found: %C, 64.22; %H, 6.71; %N, 8.82.

Mass Spectrum: M+1=319.

[α]_(D) ²⁰=+40 (c=1.0, CHCl₃).

EXAMPLE 279 (−)-N-2S-(4-(2-pyridyl)phenyl)propyl 2-propanesulfonamide

Following the procedure of Example 278 and using material fromPreparation 99 instead of material form Preparation 92 afforded 0.36 g(47%) of the title compound.

Analysis calculated for C₁₇H₂₂N₂O₂S: %C, 64.12; %H, 6.96; %N, 8.80.Found: %C, 63.93; %H, 6.86; %N, 8.65.

Mass Spectrum: M+1=319.

[α]_(D) ²⁰=−36 (c=1.0, CHCl₃).

EXAMPLE 280 N-2-(4-N-phenyloxalylamido)phenyl)propyl2-propanesulfonamide

A −78° C. solution of the material from Example 222 (0.28 9, 0.79 mmol)in THF (5 ml) was treated with phenyl magnesium bromide (0.27 ml, 0.82mmol). The reaction mixture was warmed slightly to dissolve the solid.After 1 hr additional phenyl magnesium bromide (0.27 ml, 0.82 mmol) wasadded at −78° C. and the mixture was stirred for 2 h. The reactionmixture was quenched at −78° C. with 10% solution of ammonium chloride.The organic was extracted with ether (2×20 ml). The combined organiclayers were washed with brine (10 ml), dried over magnesium sulfate andconcentrated. The crude product was further purified by flashchromatography (SiO₂, 30% EtOAc: Hexanes)to give 0.31 g (46%) of ayellow oil as the pure product. NMR was consistent with the proposedtitle structure. Field Desorption Mass Spectrum: M⁺=389.3.

EXAMPLE 281 Preparation of N-methyl-N-2-(4-(3-thienyl)phenylpropyl2-propanesulfonamide

Scheme II: To a solution of 0.5 g (1.6 mmol) ofN-2-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide (see example 103)in 5 mL of tetrahydrofuran was added 1.6 mL (1.6 mmol) of a 1 M solutionof sodium bis(trimethylsilyl)amide in tetrahydrofuran. Enoughdimethylformamide was added to solublize the resulting precipitate. Tothe mixture was added 0.3 g (1.9 mmol) of iodomethane and the reactionstirred at room temperature for 16 hours. The mixture was diluted with10 mL of ethyl acetate and washed once with 10 mL of water. The organicportion was separated and the aqueous portion was extracted two timeswith 5 mL each of ethyl acetate. The combined organics were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo.Chromatography (25 g silica gel, 25% ethyl acetate/hexane) of theresidue afforded 0.2 g (38%) of the title compound.

Analysis calculated for C₁₇H₂₃NO₂S₂: %C, 60.50; %H, 6.87; %N, 4.15.Found: %C, 60.61; %H₁, 6.86; %N, 4.17.

Electrospray Mass Spectrum: M+1=338.

In a manner analogous to the procedure described in example 281, thecorresponding N-methylated compounds are prepared from the compoundsprepared in examples 1-280.

In a manner analogous to the procedures described herein theN-acetylated compounds, such as;

are prepared by one of ordinary skill in the art by reaction of thecompounds prepared in examples 1-280 with either acetic anhydride oracetyl chloride in the presence of base, such as triethylamine (See forexample T. W. Green, “Protective Groups in Organic Synthesis”, JohnWiley & Sons, Inc., (1981) pages 251-252).

In a manner analogous to the procedures described herein the—N—CO₂C(CH₃)₃ compounds, such as;

are prepared by one of ordinary skill in the art by reaction of thecompounds prepared in examples 1-280 with di-tert-butyl dicarbonate inthe presence of base (See for example T. W. Green, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1981) pages 232-233 andSynthetic Communications, 23, 1443 (1993)).

In addition, in a manner analogous to the procedures described hereinthe —N—CO₂CH₂C₆H₅ compounds, such as;

are prepared by one of ordinary skill in the art by reaction of thecompounds prepared in examples 1-280 with benzyl chloroformate in thepresence of base (See for example T. W. Green, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, Inc., (1981) pages 239-241).

We claim:
 1. A compound of the formula:

wherein R^(a) represents (1-6C)alkyl, CO(1-6C)alkyl, CO(aryl),CO₂(1-6C)alkyl, CO₂(1-6C)alkylaryl, CO₂(aryl),CO(1-6C)alkylNH(1-6C)alkyl, or CO(1-6C)alkylN(1-6C)alkyl₂; R¹ representsa naphthyl group or a phenyl group which is unsubstituted or substitutedby one or two substituents selected independently from halogen; nitro;cyano; hydroxylmino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl;(3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl;halo(1-10C)alkyl; (CH₂)_(y)X¹R⁹ in which y is 0 or an integer of from 1to 4, X¹ represents 0, S, NR¹⁰, CO, COO, OCO, CONR¹¹, NR¹²CO, NR¹²COCOOor OCONR¹³, R⁹ represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl,(3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or(3-8C)cycloalkyl and R¹⁰, R¹¹, R¹² and R¹³ each independently representshydrogen or (1-10C)alkyl, or R⁹ and R¹⁰, R¹¹, R¹² or R¹³ together withthe nitrogen atom to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl;N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl;pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl;dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl;dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl;(1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl;tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl;benzofuryl; benzothienyl; benzimidazolyl; and a group of formulaR¹⁴—(L^(a))_(n)—X²—(L^(b))_(m) in which X² represents a bond, O, NH, S,SO, SO₂, CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH₂CONH orCH═CH, L^(a) and L^(b) each represent (1-4C)alkylene, one of n and m is0 or 1 and the other is 0, and R¹⁴ represents a phenyl or heteroaromaticgroup which is unsubstituted or substituted by one or two of halogen,nitro, cyano, hydroxylmino, (1-10C)alkyl, (2-10C)alkenyl,(2-10C)alkynyl, (3-8C)-cycloalkyl,4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl,cyano(2-10C)alkenyl, phenyl, and (CH₂)_(z)X³R¹⁵ in which z is 0 or aninteger of from 1 to 4, X³ represents O, S, NR¹⁶, CO, CH(OH), COO, OCO,CONR¹⁷, NR¹⁸CO, NHSO₂, NHSO₂NR¹⁷, NHCONH, OCONR¹⁹ or NR¹⁹COO, R¹⁵represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl,(1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl,(N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl,(3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or anaromatic or heteroaromatic group which is unsubstituted or substitutedby one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl,di(1-4C)alkylamino and (1-4C)alkoxy and R¹⁶, R¹⁷, R¹⁸ and R¹⁹ eachindependently represents hydrogen or (1-10C)alkyl, or R¹⁵ and R¹⁶, R¹⁷,R¹⁸ or R¹⁹ together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; R²represents ethyl, 2-propyl, or dimethylamino R⁵, R⁶ and R⁷ representhydrogen; and R⁸ represents methyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 wherein R^(a) is(1-6C)alkyl, CO(1-6C)alkyl, CO(aryl), CO₂(1-6C)alkyl,CO₂(1-6C)alkylaryl, or CO₂(aryl).
 3. A compound according to claim 1wherein R^(a) is (1-6C)alkyl.
 4. A compound according to claim 1 whereinR^(a) is methyl.
 5. A pharmaceutical composition, which comprises acompound as claimed in claim 1 and a pharmaceutically acceptable diluentor carrier.
 6. A method of potentiating glutamate receptor function in amammal requiring such treatment, which comprises administering aneffective amount of a compound of claim
 1. 7. A method of treating acognitive disorder; a neuro-degenerative disorder; age-related dementia;age-induced memory impairment; movement disorder; reversal of adrug-induced state; depression; attention deficit disorder; attentiondeficit hyperactivity disorder; psychosis; cognitive deficits associatedwith psychosis; or drug-induced psychosis in a patient, which comprisesadministering to a patient in need thereof an effective amount of acompound according to claim
 1. 8. A method for improving memory orlearning ability in a patient, which comprises administering to apatient in need thereof an effective amount of a compound according toclaim 1.